Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: KMT2A
SNOMEDCT: 763618001;
Cytogenetic location: 11q23.3 Genomic coordinates (GRCh38): 11:118,436,492-118,526,832 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q23.3 | Wiedemann-Steiner syndrome | 605130 | Autosomal dominant | 3 |
The KMT2A gene, or MLL, encodes a DNA-binding protein that methylates histone H3 (see 602810) lys4 (H3K4) and positively regulates expression of target genes, including multiple HOX genes (see 142980). MLL is a frequent target for recurrent translocations in acute leukemias that may be characterized as acute myeloid leukemia (AML; 601626), acute lymphoblastic leukemia (ALL), or mixed lineage (biphenotypic) leukemia (MLL). Leukemias with translocations involving MLL possess unique clinical and biologic characteristics and are often associated with poor prognosis. MLL rearrangements are found in more than 70% of infant leukemias, whether the immunophenotype is more consistent with ALL or AML6, but are less frequent in leukemias from older children. MLL translocations are also found in approximately 10% of AMLs in adults, as well as in therapy-related leukemias, most often characterized as AML, that develop in patients previously treated with topoisomerase II inhibitors for other malignancies. More than 50 different MLL fusion partners have been identified. Leukemogenic MLL translocations encode MLL fusion proteins that have lost H3K4 methyltransferase activity. A key feature of MLL fusion proteins is their ability to efficiently transform hematopoietic cells into leukemia stem cells (Krivtsov and Armstrong, 2007).
Recurring chromosomal translocations involving chromosome 11q23 have been observed in both acute lymphoid leukemia and acute myeloid leukemia (AML; 601626), especially acute monoblastic leukemia (AML-M5) and acute myelomonocytic leukemia (AMML-M4). Rowley et al. (1990) demonstrated that the breakpoints in four 11q23 translocations associated with leukemia were contained within a yeast artificial chromosome (YAC) clone bearing the CD3D (186790) and CD3G (186740) genes. Within this YAC, Ziemin-van der Poel et al. (1991) identified a transcription unit spanning the breakpoint junctions of 3 of these translocations, 4;11, 9;11, and 11;19. They described 2 other related transcripts that were upregulated in a translocation cell line. Ziemin-van der Poel et al. (1991) named the gene MLL for myeloid/lymphoid, or mixed lineage, leukemia. Cimino et al. (1991) identified the same gene and called it ALL1.
Gu et al. (1992) determined that the ALL1 gene encodes a protein of more than 3,910 amino acids containing 3 regions with homology to sequences within the Drosophila 'trithorax' gene, including cysteine-rich regions that can be folded into 6 zinc finger-like domains. Tkachuk et al. (1992) showed that the ALL1 gene, which they referred to as HRX (for 'homolog of trithorax'), codes for a 431-kD protein. Djabali et al. (1992) also cloned an 11.5-kb transcript spanning the 11q23 translocation breakpoint.
Parry et al. (1993) showed that the sequence of a partial TRX1 cDNA contained an open reading frame encoding 1,012 amino acids with extensive homology to the Drosophila trithorax protein, particularly in the zinc finger-like domains. The TRX1 gene appears to be unique in the human genome and has been conserved during evolution.
Butler et al. (1997) analyzed the distribution and localization of HRX proteins in cell lines and human tissues, using both polyclonal and monoclonal antibodies. Immunocytochemical analysis showed a punctate distribution of wildtype and chimeric HRX proteins within cell nuclei, suggesting that HRX localizes to nuclear structures in cells with and without 11q23 translocations. Nuclear staining was found in the majority of tissues studied, with the strongest reactivity in cerebral cortex, kidney, thyroid, and lymphoid tissues. Thus, Butler et al. (1997) concluded that HRX is widely expressed in most cell types, including hematopoietic cells, a finding that precludes an immunocytochemical approach for diagnosis of leukemias bearing 11q23 structural abnormalities.
Using qRT-PCR analysis in mouse retina, Brightman et al. (2018) determined that Mll1 is widely expressed in neural progenitors and in developing and differentiated neurons, particularly in the inner retina.
Gu et al. (1992) determined that the MLL gene spans approximately 100 kb and contains at least 21 exons.
The MLL gene maps to chromosome 11q23 (Ziemin-van der Poel et al., 1991; Cimino et al., 1991).
Milne et al. (2002) showed that MLL regulates target HOX gene expression through direct binding to promoter sequences. They determined that the MLL SET domain is a histone H3 (see 601128) lys4 (K4)-specific methyltransferase whose activity is stimulated with acetylated H3 peptides. This methylase activity was found to be associated with HOX gene activation and H3 K4 methylation at cis regulatory sequences in vivo. A leukemogenic MLL fusion protein that activates HOX expression had no effect on histone methylation, suggesting a distinct mechanism for gene regulation by MLL and MLL fusion proteins.
Nakamura et al. (2002) found that ALL1 is present within a stable multiprotein supercomplex composed of at least 29 proteins. The majority of the complex proteins are components of transcription complexes, including TFIID (see 604912). Other components are involved in RNA processing or histone methylation. The authors found that the complex remodels, acetylates, deacetylates, and methylates nucleosomes and/or free histones, and that the H3 K4 methylation activity of the complex is conferred by the ALL1 SET domain. Chromatin immunoprecipitations showed that ALL1 and other complex components examined were bound at the promoter of an active ALL1-dependent HOXA9 gene (142956). In parallel, H3 K4 was methylated, and histones H3 and H4 were acetylated at this promoter.
The MLL gene encodes a large nuclear protein that is required for the maintenance of HOX gene expression. MLL is cleaved at 2 conserved sites to generate an N-terminal 320-kD fragment (N320) and a C-terminal 180-kD fragment (C180), which heterodimerize to stabilize the complex and confer its subnuclear destination. Hsieh et al. (2003) purified and cloned the protease responsible for cleaving MLL, which they entitled taspase-1 (608270). They determined that taspase-1 initiates a class of endopeptidases that utilize an N-terminal threonine as the active-site nucleophile to proteolyze polypeptide substrates following aspartate. RNA interference-mediated knockdown of taspase-1 in HeLa cells resulted in the appearance of unprocessed MLL and the loss of proper HOX gene expression.
Lim et al. (2009) showed that Mll1 is required for neurogenesis in the mouse postnatal brain. Mll1-deficient subventricular zone neural stem cells survive, proliferate, and efficiently differentiate into glial lineages; however, neuronal differentiation is severely impaired. In Mll1-deficient cells, early proneural Mash1 (100790) and gliogenic Olig2 (606386) expression are preserved, but Dlx2 (126255), a key downstream regulator of subventricular zone neurogenesis, is not expressed. Overexpression of Dlx2 can rescue neurogenesis in Mll1-deficient cells. Chromatin immunoprecipitation demonstrates that Dlx2 is a direct target of MLL in subventricular zone cells. In differentiating wildtype subventricular zone cells, Mash1, Olig2, and Dlx2 loci have high levels of histone-3 trimethylated at lys4 (H3K4me3), consistent with their transcription. In contrast, in Mll1-deficient subventricular zone cells, chromatin at Dlx2 is bivalently marked by both H3K4me3 and H3K27me3, and the Dlx2 gene fails to properly activate. Lim et al. (2009) concluded that their data supported a model in which Mll1 is required to resolve key silenced bivalent loci in postnatal neural precursors to the actively transcribed state for the induction of neurogenesis, but not for gliogenesis.
Liu et al. (2010) assigned MLL as a novel effector in the mammalian S-phase checkpoint network and identified checkpoint dysfunction as an underlying mechanism of MLL leukemias. MLL is phosphorylated at ser516 by ATR (601215) in response to genotoxic stress in the S phase, which disrupts its interaction with, and hence its degradation by, the SCF(Skp2) E3 ligase (see 601436), leading to its accumulation. Stabilized MLL protein accumulates on chromatin, methylates histone H3 lysine-4 at late replication origins, and inhibits the loading of CDC45 (603465) to delay DNA replication. Cells deficient in MLL showed radioresistant DNA synthesis and chromatid-type genomic abnormalities, indicative of S-phase checkpoint dysfunction. Reconstitution of Mll-null mouse embryonic fibroblasts with wildtype but not S516A or delta-SET mutant MLL rescued the S-phase checkpoint defects. Moreover, murine myeloid progenitor cells carrying an Mll-CBP (600140) knockin allele that mimics human t(11;16) leukemia showed a severe radioresistant DNA synthesis phenotype. Liu et al. (2010) demonstrated that MLL fusions function as dominant-negative mutants that abrogate the ATR-mediated phosphorylation/stabilization of wildtype MLL on damage to DNA, and thus compromise the S-phase checkpoint. Together, Liu et al. (2010) concluded that their results identified MLL as a key constituent of the mammalian DNA damage response pathway and showed that deregulation of the S-phase checkpoint incurred by MLL translocations probably contributes to the pathogenesis of human MLL leukemias.
Zhu et al. (2015) demonstrated that p53 (191170) gain-of-function mutants bind to and upregulate chromatin regulatory genes, including the methyltransferases MLL1, MLL2 (KMT2D; 602113), and acetyltransferase MOZ (KAT6A; 601408), resulting in genomewide increases of histone methylation and acetylation. Analysis of The Cancer Genome Atlas showed specific upregulation of MLL1, MLL2, and MOZ in p53 gain-of-function patient-derived tumors, but not in wildtype p53 or p53-null tumors. Cancer cell proliferation was markedly lowered by genetic knockdown of MLL1 or by pharmacologic inhibition of the MLL1 methyltransferase complex. Zhu et al. (2015) concluded that their study revealed a novel chromatin mechanism underlying the progression of tumors with gain-of-function p53, and suggested possibilities for designing combinatorial chromatin-based therapies for treating individual cancers driven by prevalent gain-of-function p53 mutations.
Li et al. (2016) demonstrated that a minimized human RBBP5 (600697)-ASH2L (604782) heterodimer is the structural unit that interacts with and activates all MLL family histone methyltransferases (MLL1; MLL2; MLL3, 606833; MLL4, 606834; SET1A, 611052; SET1B, 611055). Their structural, biochemical, and computational analyses revealed a 2-step activation mechanism of MLL family proteins. Li et al. (2016) concluded that their findings provided unprecedented insights into the common theme and functional plasticity in complex assembly and activity regulation of MLL family methyltransferases, and also suggested a universal regulation mechanism for most histone methyltransferases.
Brightman et al. (2018) showed that mice with knockout of Mll1 in retinal progenitors display rod/cone dysfunction and deficits in visual signal transmission from photoreceptors to inner neurons. Mll1 deficiency resulted in thinner retinas, particularly affecting the inner layers, due to reduced progenitor cell proliferation and cell cycle progression. Immunostaining combined with RNAseq and histone modification analyses demonstrated that Mll1 deficiency altered retinal cell composition and caused a change in neuron-to-glia ratio. The gene expression profile of horizontal cells (HC) was one of the most severely affected in the knockout retinas, and detailed investigation revealed that Mll1 is indispensable for maintaining HC integrity, including identity, gene expression, and axon network. Mll1 knockout retinas failed to develop normal outer plexiform layer synapses, resulting in defects in visual signal transmission.
Delgado et al. (2020) found that the maintenance of neural stem cell (NSC) positional identity in the murine brain requires a Mll1-dependent epigenetic memory system. After establishment by sonic hedgehog (SHH; 600725), ventral NSC identity became independent of this morphogen. Even transient Mll1 inhibition caused a durable loss of ventral identity, resulting in the generation of neurons with the characteristics of dorsal NSCs in vivo. Delgado et al. (2020) concluded that spatial information provided by morphogens can be transitioned to epigenetic mechanisms that maintain regionally distinct developmental programs in the forebrain.
MLL Fusion Proteins
Human ML-2 leukemia cells lack a normal MLL gene and exclusively express an MLL/AF6 (MLLT4; 159559) fusion protein. Yokoyama et al. (2005) showed that MLL/AF6 associated with menin (MEN1; 613733) in ML-2 cells. Chromatin immunoprecipitation analysis showed both proteins present on upstream sites of the HOXA7 (142950), HOXA9 (142956), and HOXA10 (142957) promoters. Deletions and point mutations performed in the MLL portion of the MLL/ENL (MLLT1; 159556) fusion protein revealed a high affinity menin-binding motif (RXRFP) near the N terminus. Interaction between oncogenic MLL and menin was required for initiation of MLL-mediated leukemogenesis in mouse stem/progenitor cells, and menin was essential to maintain MLL-associated myeloid transformation. Acute genetic ablation of menin in mice reversed aberrant Hox gene expression mediated by MLL-menin promoter-associated complexes and specifically abrogated differentiation arrest and oncogenic properties of MLL-transformed leukemic blasts.
By gel filtration, mass spectrometry, and Western blot analysis of human cell lines, Nie et al. (2003) identified unique low-abundance SWI/SWF complexes that contained ENL, several common SWI/SNF subunits, and either BAF250A (ARID1A; 603024) or BAF250B (ARID1B; 614556). Western blot analysis of HB(11;19) leukemia cells, which express the oncogenic MLL/ENL fusion protein, revealed that MLL/ENL also interacted with the BAF250B-containing complex. MLL/ENL-containing SWI/SNF complexes coactivated the HOXA7 promoter in a reporter gene assay.
Crystal Structure
Huang et al. (2012) reported the crystal structures of human menin (613733) in its free form and in complexes with MLL1 or with JUND (165162), or with an MLL1-LEDGF (603620) heterodimer. These structures showed that menin contains a deep pocket that binds short peptides of MLL1 or JUND in the same manner, but that it can have opposite effects on transcription. The menin-JUND interaction blocks JUN N-terminal kinase-mediated JUND phosphorylation and suppresses JUND-induced transcription. In contrast, menin promotes gene transcription by binding the transcription activator MLL1 through the peptide pocket while still interacting with the chromatin-anchoring protein LEDGF at a distinct surface formed by both menin and MLL1.
MLL Breakpoint Cluster Region
The ALL1 gene is rearranged in acute leukemias with interstitial deletions or reciprocal translocations between chromosome 11q23 and chromosomes 1, 4, 6, 9, 10, or 19. Gu et al. (1992) cloned translocation fragments from leukemic cells from t(4;11) and showed clustering of the breakpoints in areas of 7 to 8 kb on both chromosome 4 and 11. Sequencing indicated heptamer and nonamer-like sequences, associated with rearrangements of immunoglobulin and T-cell receptor genes, near the breakpoints. This suggested a direct involvement of the VDJ recombinase in the 11q23 translocations. Gu et al. (1992) determined that the breakpoint cluster region within ALL1 spans 8 kb and encompasses several small exons, most of which begin in the same phase of the open reading frame.
McCabe et al. (1992) presented evidence that the breakpoints in all the translocations involving 11q23 in leukemia cells, e.g., t(4;11) t(6;11), t(9;11), and t(11;19), are clustered within a 9-kb BamHI genomic region of the MLL gene. McCabe et al. (1992) detected rearrangements of DNA in a fragment of the MLL gene by Southern blot hybridization. Djabali et al. (1992) concluded that most of the breakpoints in infant leukemias with t(4;11) and t(9;11) translocations lie within a 5-kb region.
Using a human TRX1 cDNA as a probe, Parry et al. (1993) demonstrated that the gene is interrupted in both infant and adult acute myeloid (AML) and lymphoid (ALL) leukemia patients with 11q23 translocations. The structure of the TRX1 gene around the breakpoints show that this part of the human gene is interrupted by 9 introns. As a result of the rearrangement, zinc finger domains are translocated in both ALL and AML patients.
Strout et al. (1998) analyzed the fusion sequences in genomic DNA from 9 patients with AML. Each had a partial tandem repeat spanning exons 2 to 6 of the ALL1 gene on 11q23. The breakpoint in intron 6 occurred in the breakpoint cluster region and the other near the 3-prime end of intron 1. In 7 cases, a distinct point of fusion could not be identified; instead, the sequence gradually diverged from an Alu element in intron 6 to an Alu element in intron 1 through heteroduplex fusion. The results supported the hypothesis that a recombination event between homologous Alu sequences is responsible for the partial tandem duplication of ALL1, probably through an intrastrand slipped-mispairing mechanism, in the majority of AML cases with this defect. This appeared to be the first demonstration identifying Alu element-mediated recombination as a consistent mechanism for gene rearrangement in somatic tissue.
MLL/AF4 Fusion Gene
Gu et al. (1992) determined that the t(4;11) chromosome translocation in leukemia results in 2 reciprocal fusion products coding for chimeric proteins derived from ALL1 and from a gene on chromosome 4 that they termed AF4 (MLLT2; 159557).
Translocations involving 11q23 in leukemia result in the translocation of zinc finger domains with fusion to other genes on chromosome 4, chromosome 9, or chromosome 19. The gene on chromosome 19 with which it is fused is ENL (159556). Nakamura et al. (1993) showed that the genes with which it is fused on chromosome 4 (AF4) and chromosome 9 (AF9; 159558) show high homology of sequence to ENL. The protein products of the AF4, AF9, and ENL proteins contained nuclear targeting sequences as well as serine-rich and proline-rich regions.
Independently, Domer et al. (1993) characterized the MLL/AF4 fusion product generated by the t(4;11) translocation. The sequence of the complete open reading frame for this fusion transcript revealed that the MLL protein is homologous to DNA methyltransferase. In the fusion gene, the 5-prime portion is derived from the MLL gene and the 3-prime portion from the AF4 gene.
Gale et al. (1997) demonstrated that unique or clonotypic MLL-AF4 genomic fusion sequences were detectable in neonatal blood spots from individuals who developed ALL at ages 5 months to 2 years, thus providing unequivocal evidence for a prenatal initiation of acute leukemia in young patients. They stated that common subtypes due to other translocation fusion genes can be expected to have a similar prenatal initiation.
In an infant diagnosed at the age of 3 weeks with ALL after presenting with hepatosplenomegaly and marked leukocytosis, Raffini et al. (2002) found a 3-way rearrangement of the MLL, AF4, and CDK6 (603368) genes. By reverse-panhandle PCR, they identified a breakpoint junction of CDK6 from band 7q21-q22 and MLL intron 9. Thus, the patient had an in-frame CDK6-MLL transcript along with an in-frame MLL-AF4 transcript.
Wang et al. (2010) studied leukemia stem cells in mouse models of acute myelogenous leukemia induced by either coexpression of the Hoxa9 (142956) and Meis1a (601739) oncogenes or by the fusion oncoprotein MLL-AF9. The authors showed that the Wnt (see 164820)/beta-catenin (116806) signaling pathway is required for self-renewal of leukemia stem cells that are derived from either hematopoietic stem cells or more differentiated granulocyte-macrophage progenitors. Because the Wnt/beta-catenin pathway is normally active in hematopoietic stem cells but not in granulocyte-macrophage progenitors, Wang et al. (2010) concluded that reactivation of beta-catenin signaling is required for the transformation of progenitor cells by certain oncogenes. Beta-catenin is not absolutely required for self-renewal of adult hematopoietic stem cells; thus, targeting the Wnt/beta-catenin pathway may represent a new therapeutic opportunity in acute myelogenous leukemia.
MLL/ENL Fusion Gene
In studies of a t(11;19)-carrying cell line, Tkachuk et al. (1992) identified fusion transcripts expressed from both derivative chromosomes. The more abundant derivative 11 transcript coded for a chimeric protein containing the amino terminal 'AT-hook' motifs of the HRX gene fused to the ENL gene (MLLT1; 159556) from chromosome 19. (ENL was so named for '11-19 leukemia.') The HRX protein may have effects mediated by DNA binding within the minor groove at AT-rich sites. Tkachuk et al. (1992) referred to this type of leukemia as representing the multilineage leukemias rather than mixed lineage leukemias. The cell line carrying the t(11;19) was from a patient with T-cell precursor acute lymphocytic leukemia (Smith et al., 1989).
Translocations involving 11q23 in leukemia result in the translocation of zinc finger domains with fusion to other genes on chromosome 4, chromosome 9, or chromosome 19. The gene on chromosome 19 with which it is fused is ENL. Nakamura et al. (1993) showed that the genes with which it is fused on chromosome 4 (AF4) and chromosome 9 (AF9; 159558) show high homology of sequence to ENL. The protein products of the AF4, AF9, and ENL proteins contained nuclear targeting sequences as well as serine-rich and proline-rich regions.
MLL/AF9 Fusion Gene
Translocations involving 11q23 in leukemia result in the translocation of zinc finger domains with fusion to other genes on chromosome 4, chromosome 9, or chromosome 19. The gene on chromosome 19 with which it is fused is ENL. Nakamura et al. (1993) showed that the genes with which it is fused on chromosome 4 (AF4) and chromosome 9 (AF9; 159558) show high homology of sequence to ENL. The protein products of the AF4, AF9, and ENL proteins contained nuclear targeting sequences as well as serine-rich and proline-rich regions.
The human AF9 gene is one of the most common fusion partner genes with MLL, resulting in the t(9;11)(p22;q23). Strissel et al. (2000) identified several different structural elements in AF9, including a colocalizing DNA topo II cleavage site and a DNase I hypersensitive (DNase I HS) site. In addition, 2 scaffold-associated regions (SARs) are located centromeric to the topo II and DNase I HS cleavage sites and border breakpoint regions in 2 leukemic cell lines. The authors thus demonstrated that the patient breakpoint regions of AF9 share the same structural elements as the MLL BCR, and they proposed a DNA breakage and repair model for nonhomologous recombination between MLL and its partner genes, particularly AF9.
MLL/AF6 Fusion Gene
Prasad et al. (1993) identified AF6 (MLLT4; 159559) as the fusion partner of MLL in a common translocation, t(6;11)(q27;q23), associated with leukemia. The t(6;11)(q27;q23) translocation results in a chimeric MLL/AF6 protein with a calculated molecular mass of 325 kD. In the chimeric protein, the N-terminal portion of MLL, including 3 AT hook motifs, is fused to all of AF6 except the first 35 amino acids, leaving the Ras-interacting domain and the DHR motif of AF6 intact. By Western blot analysis of transfected COS cells and a human cell line with the t(6;11)(q27;q23) translocation, Joh et al. (1997) found that the MLL/AF6 fusion protein had an apparent molecular mass of 360 kD. Immunolocalization and cell fractionation followed by Western blot analysis indicated that MLL/AF6 was targeted to the nucleus, whereas AF6 itself was cytoplasmic. Mutation analysis indicted that the region of MLL containing AT hook motifs was responsible for the nuclear localization of the chimeric protein.
MLL/GPH Fusion Gene
Eguchi et al. (2001) found that the gephyrin gene (GPH; 603930) can partner with MLL in leukemia associated with the translocation t(11;14)(q23;q24). The child in whom this translocation was discovered showed signs of acute undifferentiated leukemia 3 years after intensive chemotherapy that included the topoisomerase II inhibitor VP16. The AT hook motifs and a DNA methyltransferase homology domain of the MLL gene were fused to the C-terminal half of GPH, including a presumed tubulin-binding site and a domain homologous to the E. coli molybdenum cofactor biosynthesis protein. Eguchi et al. (2001) suggested that MLL-GPHN may have been generated by the chemotherapeutic agent, followed by error-prone DNA repair via nonhomologous end-joining.
MLL/GMPS Fusion Gene
In a patient with treatment-related acute myeloid leukemia and the karyotype t(3;11)(q25;q23), Pegram et al. (2000) identified GMPS (600358) to be the partner gene of MLL. The authors stated that GMPS was the first partner gene of MLL to be identified on 3q and the first gene of this type to be found in leukemia-associated translocations.
MLL/FBP17 Fusion Gene
Fuchs et al. (2001) reported fusion of the gene encoding formin-binding protein-17 (FBP17; 606191) to MLL in a child with acute myelogeneous leukemia and a complex chromosome rearrangement, ins(11;9)(q23;134)inv(11)(q13q23). The fused mRNA was represented by MLL at the 5-prime end and FBP17 at the 3-prime end.
MLL/LPP Fusion Gene
By FISH and Southern blot analyses, Daheron et al. (2001) identified a rearrangement in the mixed lineage leukemia gene due to a novel t(3;11)(q28;q23) translocation in a patient who developed acute myeloid leukemia of the M5 type 3 years after treatment for a follicular lymphoma. Through inverse PCR, they identified the LPP gene (600700) on 3q28 as the MLL fusion partner. The breakpoint occurred in intron 8 of MLL and LPP. They found that the MLL/LPP and LPP/MLL predicted proteins contain many of the features present in other MLL rearrangements.
MLL/PNUTL1 Fusion Gene
Megonigal et al. (1998) examined the MLL genomic translocation breakpoint in acute myeloid leukemia of infant twins. Southern blot analysis showed 2 identical MLL gene rearrangements indicating chromosomal translocation. The rearrangements were detected in the second twin before signs of clinical disease and the intensity relative to the normal fragment indicated that the translocation was not constitutional. Fluorescence in situ hybridization with an MLL-specific probe and karyotype analyses suggested that a t(11;22)(q23;q11.2) disrupted MLL. Megonigal et al. (1998) used panhandle variant PCR to clone the translocation breakpoint and identified a region of 22q11.2 involved in both leukemia and a constitutional disorder. By ligating a single-stranded oligonucleotide that was homologous to known 5-prime MLL genomic sequence to the 5-prime ends of BamHI-digested DNA through a bridging oligonucleotide, they formed the stem-loop template for panhandle variant PCR, which yielded products of 3.9 kb. The MLL genomic breakpoint was in intron 7. The sequence of the partner DNA from 22q11.2 was identical to the human CDCrel (cell division cycle-related) gene (PNUTL1; 602724) that maps to chromosome 22. Both MLL and PNUTL1 contained homologous CT, TTTGTG, and GAA sequences within a few basepairs of their respective breakpoints, which may have been important in uniting these 2 genes by translocation. RT-PCR amplified an in-frame fusion of MLL exon 7 to PNUTL1 exon 3, indicating that a chimeric mRNA had been transcribed.
MLL/CDK6 Fusion Gene
In an infant diagnosed at the age of 3 weeks with acute lymphoblastic leukemia (ALL; 613065) after presenting with hepatosplenomegaly and marked leukocytosis, Raffini et al. (2002) found a 3-way rearrangement of the MLL, AF4, and CDK6 (603368) genes. By reverse-panhandle PCR, they identified a breakpoint junction of CDK6 from band 7q21-q22 and MLL intron 9. Thus, the patient had an in-frame CDK6-MLL transcript along with an in-frame MLL-AF4 transcript.
MLL/LASP1 Fusion Gene
Strehl et al. (2003) identified a new MLL fusion partner on chromosome 17q in the case of an infant with AML-M4 and a t(11;17)(q23;q21) translocation. FISH and RT-PCR analyses indicated a rearrangement of the MLL gene, but no fusion with previously identified MLL fusion partners at 17q, such as AF17 (600328) or MSF (604061). RACE revealed an in-frame fusion of MLL to LASP1 (602920), a gene that is amplified and overexpressed in breast cancer. The authors stated that retroviral transduction of myeloid progenitors demonstrated that MLL/LASP1 was the fourth known fusion of MLL with a cytoplasmic protein that has no in vitro transformation capability, the others being GRAF (605370), ABI1 (603050), and FBP17.
MLL/LAF4 Fusion Gene
Von Bergh et al. (2002) identified an MLL/LAF4 (601464) fusion gene in an infant with ALL and a t(2;11)(p15;p14) translocation. Bruch et al. (2003) also reported an infant with ALL and an MLL/LAF4 fusion caused by an ins(11;2)(q23;q11.2q11.2) insertion.
MLL/LARG Fusion Gene
In a patient with primary acute myeloid leukemia and a complex karyotype, Kourlas et al. (2000) found that the 5-prime end of MLL at exon 6 was fused in-frame with the 3-prime end of almost the entire open reading frame of the LARG gene (604763), which lies on 11q23. Transcriptional orientation of both genes at 11q23 was found to be from centromere to telomere, consistent with other data that suggested that the MLL/LARG fusion resulted from an interstitial deletion rather than a balanced translocation.
MLL/CBL Fusion Gene
Fu et al. (2003) found that the CBL gene (165360), which lies telomeric to MLL on 11q23, was fused to MLL in an adult patient with de novo acute myeloid leukemia (FAB M1). MLL exon 6 was fused in-frame with CBL exon 8. The genomic junction region involved the fusion of the 3-prime portion of an Alu element in intron 6 of MLL with the 5-prime portion of an Alu element in intron 7 of CBL. The absence of extensive sequence similarity at both breakpoints of MLL and CBL indicated that the recombination was not generated through homologous recombination. The transcriptional orientation of both genes is from centromere to telomere. The results of Southern blot analysis in conjunction with FISH suggested that the MLL/CBL fusion was the result of an interstitial deletion. CBL was the second MLL fusion partner identified on 11q23, the first being the LARG gene. Fu et al. (2003) stated that at least 34 partner genes for MLL had been identified.
MLL/AF10 Fusion Gene
Tanabe et al. (1996) identified an invins(10;11)(p12;q23q12) and other complex chromosomal rearrangements in a 2-year old boy with acute monoblastic leukemia (AML-M5). Cloning of the proximal 10p breakpoint showed that the MLL gene at chromosome 11q23 was fused to the 3-prime portion of AF10 (MLLT10; 602409) at chromosome 10p12. Cloning of the telomeric 10p junction revealed that the 5-prime portion of AF10 was fused with the HEAB gene (608757). The 5-prime AF10/HEAB fusion transcript was out of frame, while the MLL/3-prime AF10 fusion was in frame.
MLL/AF15q14 and MLL/MPFYVE Fusion Genes
Hayette et al. (2000) described a 48-year-old man with AML-M4 who was cytogenetically characterized as 46,XY,-3,t(11;15)(q23;q1 4),+mar. The bone marrow was hypercellular, with 80% blast cells. The patient was treated by intensive chemotherapy and died 4 month after diagnosis. The translocation resulted in a in-frame fusion between exon 8 of the MLL gene and exon 10 of the AF15q14 gene (609173). The fusion transcript was predicted to encode a 1,503-amino acid protein composed of 1,418 N-terminal amino acids of MLL and 85 C-terminal amino acids of AF15q14, including the bipartite nuclear localization signal.
Kuefer et al. (2003) identified a similar t(11;15)(q23;q14) in a 3-year-old boy with de novo T-cell acute lymphoblastic leukemia. In this translocation, exon 9 of the MLL gene was fused in-frame to exon 12 of the AF15q14 gene. The deduced 1,886-amino acid fusion protein, which contains the N terminus of MLL up to lys1362 fused to the entire C terminus of AF15q14 starting from residue ile1819, has a calculated molecular mass of 208 kD. It differs from the fusion protein described by Hayette et al. (2000) in that it has a coiled-coil domain but no nuclear localization signal.
In an 11-year-old boy with AML-M2 and a translocation t(11;15)(q23;q14), Chinwalla et al. (2003) identified MLL-AF15q14 and MLL-MPFYVE (619635) fusion transcripts. Both fusion transcripts were in-frame and had the potential to encode novel fusion proteins.
MLL/CIP29 Fusion Gene
In an infant with AML-M4, Hashii et al. (2004) identified a translocation, t(11;12)(q23;q13), in which the coding region of the CIP29 gene (610049) was fused in-frame to exon 9 of the MLL gene. The fusion protein had the N-terminal AT hooks and central DNA methyltransferase homology region of MLL fused to nearly all of the CIP29 protein, including the N-terminal SAP domain and 2 C-terminal nuclear localization signals. RT-PCR confirmed expression of the fusion transcript in patient peripheral blood mononuclear cells.
MLL/SEPT6 Fusion Gene
Kadkol et al. (2006) described an infant with AML who had a rearrangement between chromosomes 11q23 and Xq24. FISH analysis showed a break in MLL, and RT-PCR analysis confirmed expression of an MLL/SEPT6 (300683) fusion transcript.
MLL/MAML2 Fusion Gene
Nemoto et al. (2007) isolated MLL/MAML2 (607537) fusion transcripts from secondary AML and myelodysplastic syndrome (MDS) cells with inv(11)(q21q23). RT-PCR revealed that exon 7 of MLL was fused to exon 2 of MAML2 in the AML and MDS cells. The inv(11)(q21q23) resulted in a chimeric RNA encoding a putative fusion protein containing 1,408 amino acids from the N-terminal part of MLL and 952 amino acids from the C-terminal part of MAML2. The N-terminal part of MAML2, a basic domain that includes a binding site for the NOTCH (see NOTCH1; 190198) intracellular domain, was deleted in MLL/MAML2. The MLL/MAML2 fusion protein in secondary AML and MDS and the MECT1/MAML2 fusion protein in mucoepithelioid carcinoma, benign Warthin tumor, and clear cell hidradenoma contained the same C-terminal part of MAML2. Reporter gene assays revealed that MLL/MAML2 suppressed HES1 (139605) promoter activation by the NOTCH1 intracellular domain.
MLL/GRAF Fusion Gene
Borkhardt et al. (2000) found that the GRAF gene (605370) was fused with MLL in a unique t(5;11)(q31;q23) that occurred in an infant with juvenile myelomonocytic leukemia.
MLL/ABI1 Fusion Gene
Taki et al. (1998) analyzed a patient with AML and t(10;11)(p11.2;q23) and identified, as a fusion partner with MLL, the gene ABI1 (603050) on 10p11.2. The ABI1 gene bore no homology with partner genes of MLL previously described, but the ABI1 protein exhibited sequence similarity to protein of homeotic genes, contained several polyproline stretches, and included a Src homology-3 (SH3) domain at the C terminus. The MLL-ABI1 fusion transcript in this patient was formed by an alternatively spliced ABI1. In-frame MLL-ABI1 fusion transcripts combined the MLL AT-hook motifs and DNA methyltransferase homology region with the homeodomain homologous region, polyproline stretches, and SH3 domain of the alternatively spliced transcript of ABI1.
MLL/KIAA1524 Fusion Gene
Coenen et al. (2011) identified the karyotype 46,XX,t(3;11)(q12-13;q23) in bone marrow of a 4-month-old Caucasian girl who presented with the M5 subtype of AML and central nervous system involvement. The patient died 9 weeks after diagnosis. The translocation resulted in fusion of intron 10 of the MLL gene on chromosome 11 to intron 16 of the KIAA1524 gene (610643) on chromosome 3. The 2 genes are transcribed in opposite orientations, suggesting that the translocation also required a microinversion. RT-PCR analysis confirmed expression of the fusion transcript, which was predicted to encode a 1,673-amino acid protein containing the N-terminal AT-hook domain, subnuclear localization sites, and methyltransferase domain of MLL fused to the C-terminal coiled-coil domain of KIAA1524.
MLL/FRYL Fusion Gene
Hayette et al. (2005) identified AF4p12 (FRYL; 620798) as the fusion partner of MLL in a patient with treatment-related ALL and a t(4;11)(p12;q23) translocation. In-frame fusion between MLL exon 6 and AF4p12 exon 49 resulted in a fusion transcript encoding a putative chimeric protein of 2,074 amino acids, containing 1,362 amino acids from the N-terminal part of MLL and 712 amino acids from the C-terminal part of AF4p12, including the second leucine zipper motif. Luciferase reporter analysis showed that the C-terminal part of AF4p12 fused to MLL displayed transcriptional activation potential when transiently expressed in HeLa cells.
MLL Duplication
In a study of patients with acute leukemia but no microscopically visible change at 11q23, Schichman et al. (1994) found molecular evidence of partial duplication of the ALL1 gene. The direct tandem duplication involved a region spanning exons 2 to 6, and a partially duplicated protein gene product was demonstrated. Thus, the ALL1 gene is leukemogenic when it fuses with itself as well as when it fuses with one of the genes on other chromosomes.
In addition to the translocations involving fusion of the ALL1 gene with genes on other chromosomes producing acute lymphoblastic and myelogenous leukemia, the ALL1 gene undergoes self-fusion in acute myeloid leukemias with normal karyotype or trisomy 11. In addition, Baffa et al. (1995) reported rearrangement of the ALL1 gene in a gastric carcinoma cell line. A complex, 3-way translocation involving chromosomes 1 and 11 and resulting in partial duplication of the ALL1 gene was found. Sequencing of RT-PCR products and Northern blot analysis show that only the partially duplicated ALL1 gene was transcribed, producing an mRNA with exon 8 fused to exon 2. Thus, ALL1 gene rearrangement may play a role in the pathogenesis of some solid malignancies. The absence of the normal transcript in this cell line, in association with loss of heterozygosity on 11q23 seen in solid tumors, suggests that ALL1 is involved in tumorigenesis by a loss-of-function mechanism.
Approximately 90% of adult patients with de novo AML and trisomy 11 (+11) as a sole abnormality and 11% of adult patients with de novo AML and normal cytogenetics carry a molecular rearrangement of the ALL1 gene. The rearranged ALL1 gene results from the direct tandem duplication of a portion of ALL1 itself. Caligiuri et al. (1997) showed that in cytogenetically normal cases of AML and cases with +11 as the sole cytogenetic abnormality, only 1 chromosome contains the mutated ALL1 allele. Thus, a single mutated ALL1 allele with the partial tandem duplication is sufficient for ALL1-associated leukemogenesis, irrespective of the number of normal genes present. The frequently occurring specific association of +11 and ALL1 gene mutation in the leukemic clone remained unexplained.
Detection of MLL Rearrangements
Thirman et al. (1993) demonstrated that MLL gene rearrangements can be detected with a single probe and a single restriction-enzyme digest. The ability to detect an MLL gene rearrangement rapidly and reliably, especially in patients with limited material for cytogenetic analysis, should make it possible to identify patients who have a poor prognosis and therefore require aggressive chemotherapy or marrow transplantation.
The MLL gene spans the breakpoint in translocations involving 11q23, which are responsible for approximately 70% of AML and ALL in infants and are also observed in treatment-related leukemias, especially in patients previously treated with drugs inhibiting topoisomerase II (Gibbons et al., 1990; Thirman et al., 1993).
In 15 of 26 AML cases in infants, Sorensen et al. (1994) found rearrangement of the MLL gene at the molecular level. These rearrangements were clustered within an 11-kb region containing 9 exons of the gene. In 14 of the 15 cases with rearrangements, the leukemia was associated with myelomonocytic or monocytic phenotypes (M4 or M5 FAB subtypes, respectively), both of which are associated with a poor prognosis in childhood AML. In contrast, only 1 of 11 nonrearranged cases had an M4 or M5 phenotype. Rearrangement also correlated significantly with hyperleukocytosis, another clinical parameter associated with poor outcome.
Kobayashi et al. (1993) described a case of acute lymphoblastic leukemia in a 44-year-old woman after adjuvant chemotherapy of breast cancer; they demonstrated rearrangement of the HRX gene.
Acute lymphoblastic leukemias carrying a chromosomal translocation involving the MLL gene have a particularly poor prognosis. Armstrong et al. (2002) showed that they have a characteristic, highly distinct gene expression profile that is consistent with an early hematopoietic progenitor expressing select multilineage markers and individual HOX genes. Clustering algorithms showed that lymphoblastic leukemias with MLL translocations can clearly be separated from conventional acute lymphoblastic and acute myelogenous leukemias. Armstrong et al. (2002) proposed that they constitute a distinct disease, denoted as MLL, and showed that the differences in gene expression are robust enough to classify leukemias correctly as MLL versus acute lymphoblastic leukemia or acute myelogenous leukemia. Establishing that MLL is a unique entity is critical, as it mandates the examination of selectively expressed genes for urgently needed molecular targets.
Chromosomal translocations involving the MLL gene occur in about 80% of infant leukemias. Epidemiologic studies have suggested that maternal exposure to various substances such as pesticides, marijuana, or an excess of flavonoids (naturally occurring inhibitors of topoisomerase II) might be associated with acute leukemia in infants (Ross et al., 1994). In search of possible agents inducing infant leukemia, Strick et al. (2000) investigated bioflavonoids, natural substances in food as well as in dietary supplements, that cause site-specific DNA cleavage in the MLL breakpoint cluster region (BCR) in vivo. The MLL BCR DNA cleavage was shown in primary progenitor hematopoietic cells from healthy newborns and adults as well as in cell lines; it colocalized with the MLL BCR cleavage site induced by chemotherapeutic agents, such as etoposide (VP16) and doxorubicin (Dox). Both in vivo and additional in vitro experiments demonstrated topoisomerase II (TOP2A; 126430) as the target of bioflavonoids similar to the 2 chemotherapeutic agents. Based on 20 bioflavonoids tested, Strick et al. (2000) identified a common structure essential for topoisomerase II cleavage. The authors' observations supported a 2-stage model of cellular processing of topoisomerase II inhibitors: the first and reversible stage of this cleavage resulted in DNA repair, but also rarely in chromosome translocations; whereas the second, nonreversible stage led to cell death because of an accumulation of DNA damage. These results suggested that maternal ingestion of bioflavonoids may induce MLL breaks and potentially translocations in utero leading to infant and early childhood leukemia. Strick et al. (2000) concluded that although bioflavonoids may be beneficial in certain circumstances, a potential counterbalancing disadvantage is their possible role in causing chromosome translocations leading to leukemia in all age groups, analogous to the translocation forms of AML and ALL after cancer chemotherapy. Ross (2000) commented on the observations of Strick et al. (2000) in the context of clinical and epidemiologic findings on childhood leukemia.
Wang et al. (2008) reported pharmacologic, physiologic, and genetic studies that demonstrated an oncogenic requirement for glycogen synthase kinase-3 (GSK3; see 606784) in the maintenance of a specific subtype of poor prognosis human leukemia, genetically defined by mutations of the MLL protooncogene. In contrast to its previously characterized roles in suppression of neoplasia-associated signaling pathways, GSK3 paradoxically supports MLL leukemia cell proliferation and transformation by a mechanism that ultimately involves destabilization of the cyclin-dependent kinase inhibitor p27(KIP1) (600778). Inhibition of GSK3 in a preclinical murine model of MLL leukemia provided promising evidence of efficacy and earmarked GSK3 as a candidate cancer drug target.
By whole-exome sequencing in 4 patients with Wiedemann-Steiner syndrome (605130), Jones et al. (2012) identified 3 different heterozygous de novo truncating mutations, all within exon 27 of the MLL gene (159555.0001-159555.0003) in 3 of the 4 patients. Analysis of MLL in 2 additional patients with a similar phenotype revealed heterozygosity for 2 more de novo truncating mutations (159555.0004 and 159555.0005). The variants were confirmed by Sanger sequencing, and none were found in the dbSNP or 1000 Genomes Project databases, in 600 unrelated control exome profiles, or in DNA from the unaffected parents.
In 6 unrelated children with WDSTS, Miyake et al. (2016) identified 6 different heterozygous mutations in the KMT2A gene (see, e.g., 159555.0006-159555.0008). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were demonstrated to have occurred de novo in 4 of the patients; complete parental DNA was not available for 2 patients. Four of the mutations resulted in nonsense or frameshift mutations, whereas 2 were missense mutations affecting highly conserved residues. Functional studies of the variants and studies of patient cells were not performed.
Yu et al. (1995) reported that Mll deletion in mice was embryonic lethal. Mll +/- mice had retarded growth, hemopoietic abnormalities, and bidirectional homeotic transformation of the axial skeleton, as well as sternal malformations.
Yamashita et al. (2006) examined the role of MLL in the immune system using Mll +/- mice. Mll +/- Cd4-positive T cells differentiated normally into antigen-specific effector Th1 and Th2 cells in vitro, but the ability of memory Th2 cells to produce Th2 cytokines was dramatically decreased. Histone methylation and acetylation at Th2 cytokine gene loci was not maintained in Mll +/- memory Th2 cells. Levels of Gata3 (131320) mRNA were normal in Mll +/- effector Th2 cells, but they were substantially decreased in Mll +/- memory Th2 cells; mRNA levels of other transcription factors were not affected in Mll +/- memory Th2 cells. Histone modifications of Gata3 were also aberrant in Th2 cell lines in which Mll expression had been knocked down by small interfering RNA. Ovalbumin-induced allergic eosinophilic inflammation was reduced in Mll +/- Th2 cell-transferred mice. Yamashita et al. (2006) concluded that MLL plays a crucial role in control of memory Th2 cell responses by maintaining expression of GATA3 and production of Th2 cytokines.
Barabe et al. (2007) demonstrated that upon transplantation into immunodeficient mice, primitive human hematopoietic cells expressing a mixed-lineage leukemia (MLL) fusion gene generated myeloid or lymphoid acute leukemias, with features that recapitulated human diseases. Analysis of serially transplanted mice revealed that the disease is sustained by leukemia-initiating cells that have evolved over time from a primitive cell type with a germline immunoglobulin heavy chain (IgH) gene configuration to a cell type containing rearranged IgH genes. The leukemia-initiating cells retained both myeloid and lymphoid lineage potential and remained responsive to microenvironmental cues. Barabe et al. (2007) concluded that the properties of these cells provide a biologic basis for several clinical hallmarks of MLL leukemias.
McMahon et al. (2007) found that fetal liver from Mll-knockout mouse embryos showed defects in the hematopoietic stem and progenitor pool, including reductions in long-term and short-term hematopoietic stem cell numbers and a decrease in the quiescent hematopoietic stem cell fraction. Adult mice with conditional Mll knockout had no apparent abnormalities in mature hematopoietic cells in bone marrow, spleen, and thymus. However, conditional Mll-knockout bone marrow cells produced reduced numbers of colony-forming units and showed reduced ability to compete in hematopoietic reconstitution assays. McMahon et al. (2007) concluded that MLL has a critical role in regulating stem cell self-renewal.
In a 6-year-old boy (WSS-1) with Wiedemann-Steiner syndrome (WDSTS; 605130), Jones et al. (2012) identified heterozygosity for a de novo 4-bp deletion (8806_8809del) in exon 27 of the MLL gene, predicted to cause a frameshift and premature termination (Val2936Ter). The mutation was not found in the unaffected parents, in the dbSNP or 1000 Genomes Project databases, or in 600 unrelated control exome profiles.
In an 8-year-old girl (WSS-2) with Wiedemann-Steiner syndrome (WDSTS; 605130), Jones et al. (2012) identified heterozygosity for a de novo 1-bp deletion (8267del) in exon 27 of the MLL gene, predicted to cause a frameshift and premature termination (Leu2756Ter). The mutation was not found in the unaffected parents, in the dbSNP or 1000 Genomes Project databases, or in 600 unrelated control exome profiles.
In a 12-year-old girl (WSS-3) with Wiedemann-Steiner syndrome (WDSTS; 605130), Jones et al. (2012) identified heterozygosity for a de novo 1-bp deletion (6913del) in exon 27 of the MLL gene, predicted to cause a frameshift and premature termination (Ser2305LeufsTer2). The mutation was not found in the unaffected parents, in the dbSNP or 1000 Genomes Project databases, or in 600 unrelated control exome profiles. The level of MLL transcript in patient skin fibroblasts was reduced in comparison to unrelated healthy controls, indicating nonsense-mediated decay.
In an 8-year-old boy (WSS-5) with Wiedemann-Steiner syndrome (WDSTS; 605130), Jones et al. (2012) identified heterozygosity for a de novo 7144C-T transition in exon 27 of the MLL gene, resulting in an arg2382-to-ter (R2382X) substitution. The mutation was not found in the unaffected parents, in the dbSNP or 1000 Genomes Project databases, or in 600 unrelated control exome profiles.
In a 24-year-old woman (WSS-6) with Wiedemann-Steiner syndrome (WDSTS; 605130), Jones et al. (2012) identified heterozygosity for a de novo 1-bp duplication (4599dup) in the MLL gene, predicted to cause a frameshift and premature termination (Lys1534Ter). The mutation was not found in the unaffected parents, in the dbSNP or 1000 Genomes Project databases, or in 600 unrelated control exome profiles.
In a 3-year-old Japanese boy (patient 1) with Wiedemann-Steiner syndrome (WDSTS; 605130), Miyake et al. (2016) identified a de novo heterozygous c.7438C-T transition (c.7438C-T, NM_001197104.1) in the KMT2A gene, resulting in an arg2480-to-ter (R2480X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 137/138), Exome Variant Server, 1000 Genomes Project, or in 575 in-house control exomes. Functional studies of the variant and studies of patient cells were not performed.
In a 4-year-old Australian boy (patient 3) with Wiedemann-Steiner syndrome (WDSTS; 605130), Miyake et al. (2016) identified a de novo heterozygous c.3566G-A transition (c.3566G-A, NM_001197104.1) in the KMT2A gene, resulting in a cys1189-to-tyr (C1189Y) substitution at a highly conserved residue in the CXXC zinc finger domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 137/138), Exome Variant Server, 1000 Genomes Project, or in 575 in-house control exomes. Functional studies of the variant and studies of patient cells were not performed.
In a 3-year-old Japanese girl (patient 5) with Wiedemann-Steiner syndrome (WDSTS; 605130), Miyake et al. (2016) identified a de novo heterozygous 1-bp deletion (c.1038delA, NM_001197104.1) in the KMT2A gene, predicted to result in a frameshift and premature termination (Val347LeufsTer53) in the N-terminal region of the protein. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 137/138), Exome Variant Server, 1000 Genomes Project, or in 575 in-house control exomes. Functional studies of the variant and studies of patient cells were not performed.
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