Alternative titles; symbols
HGNC Approved Gene Symbol: MYH9
SNOMEDCT: 712922002;
Cytogenetic location: 22q12.3 Genomic coordinates (GRCh38): 22:36,281,280-36,387,967 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q12.3 | Deafness, autosomal dominant 17 | 603622 | Autosomal dominant | 3 |
| Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss | 155100 | Autosomal dominant | 3 |
Saez et al. (1990) provided a molecular genetic characterization of a human nonmuscle myosin heavy chain expressed in fibroblasts, endothelial cells, and macrophages. The deduced 1,247-amino acid was weakly homologous (33%) to sarcomeric MHC, but about 72% identical to smooth muscle MHC. In contrast to vertebrate sarcomeric MHCs, which generate diversity through the expression of members of a multigene family, an alternative polyadenylation site is used in the nonmuscle MHC gene to generate multiple transcripts that encode the same protein.
D'Apolito et al. (2002) cloned mouse Myh9. The deduced 1,960-amino acid protein shares 98% identity with human MYH9. Northern blot analysis detected abundant Myh9 expression in mouse liver, spleen, lung, and kidney, but not in skeletal muscle or testis.
Toothaker et al. (1991) observed that antisera raised against the peptide made from the predicted amino acid sequence specifically reacted with a 224-kD polypeptide in leukocyte cell lines, and the protein was upregulated during the induction of monocytic and granulocytic differentiation in these cells. The cellular myosin heavy chain may be the major contractile protein responsible for movement in myeloid cell lines because no mRNA for sarcomeric myosin heavy chains is detected in these cells.
By screening mouse T-cell cDNA for myosin family members, followed by Western blot analysis, Jacobelli et al. (2004) found that Myh9 was the only class II nonmuscle myosin readily and highly detectable. Time-lapse fluorescence microscopy demonstrated that, during T-cell crawling, Myh9 expression was enriched in the uropod. After encounter with antigen on antigen-presenting cells (APCs), Myh9 redistributed to the T-cell-APC interface upon formation of the immunologic synapse. Further imaging and siRNA analysis showed that Myh9 was required for T-cell uropodal morphology, but not for synapse formation. TCR-induced phosphorylation of Myh9 in its multimerization domain indicated that inactivation of the myosin motor may be a key step in the T-cell 'stop' response during antigen recognition.
Chung and Kawamoto (2004) identified an intronic region that they designated 32kb-150, located 32 kb downstream of the transcription start sites in the human NMHCA gene, as a transcriptional regulatory region. Among IRF proteins tested, only IRF2 (147576) bound to the interferon-stimulated response element (ISRE) within 32kb-150 in vitro and in HeLa cells and mouse fibroblasts. IRF2 acted as a transcriptional activator in a reporter gene assay. The phorbol ester TPA, which triggers differentiation of human promyelocytic HL-60 cells into macrophages, upregulated expression of both NMHCA and IRF2. Chung and Kawamoto (2004) concluded that IRF2 contributes to transcriptional activation of the NMHCA gene via 32kb-150 during TPA-induced differentiation of HL-60 cells.
Wilson et al. (2010) showed that nonmuscle myosin II has a direct role in actin network disassembly in crawling cells. In fish keratocytes undergoing motility, myosin II is concentrated in regions at the rear with high rates of network disassembly. Activation of myosin II by ATP in detergent-extracted cytoskeletons resulted in rear-localized disassembly of the actin network. Inhibition of myosin II activity and stabilization of actin filaments synergistically impeded cell motility, suggesting the existence of 2 disassembly pathways, one of which requires myosin II activity. Wilson et al. (2010) concluded that their results established the importance of myosin II as an enzyme for actin network disassembly, and proposed that gradual formation and reorganization of an actomyosin network provides an intrinsic destruction timer, enabling long-range coordination of actin network treadmilling in motile cells.
Arii et al. (2010) showed that nonmuscle myosin heavy chain IIA (NMHC-IIA), a subunit of nonmuscle myosin IIA (NM-IIA), functions as a herpes simplex virus-1 (HSV-1) entry receptor by interacting with glycoprotein B. A cell line that is relatively resistant to HSV-1 infection became highly susceptible to infection by this virus when NMHC-IIA was overexpressed. Antibody to NMHC-IIA blocked HSV-1 infection in naturally permissive target cells. Furthermore, knockdown of NMHC-IIA in the permissive cells inhibited HSV-1 infection as well as cell-cell fusion when glycoproteins B, D, H, and L were coexpressed. Cell surface expression of NMHC-IIA was markedly and rapidly induced during the initiation of HSV-1 entry. NMHC-IIA is ubiquitously expressed in various human tissues and cell types and, therefore, is implicated as a functional glycoprotein B receptor that mediates broad HSV-1 infectivity both in vitro and in vivo.
Using immunofluorescence microscopy, Western blot analysis, and knockdown strategies with human lung fibroblasts, Hanisch et al. (2011) showed that Salmonella entered nonphagocytic cells by manipulating 2 machineries of actin-based motility in the host: actin polymerization through the ARP2/3 complex (604221), and actomyosin-mediated contractility in a myosin IIA- and myosin IIB-dependent manner. Hanisch et al. (2011) concluded that Salmonella entry can be effected independently of membrane ruffling.
Schramek et al. (2014) used a direct in vivo RNA interference (RNAi) strategy to screen for genes that upon repression predispose mice to squamous cell carcinomas. Tissue-specific Myh9 RNA interference and Myh9 knockout triggered invasive squamous cell carcinoma formation on tumor-susceptible backgrounds. In human and mouse keratinocytes, myosin IIa's function was manifested not only in conventional actin-related processes but also in regulating posttranscriptional p53 (191170) stabilization. Myosin IIa was diminished in human squamous cell carcinomas with poor survival, which suggested that in vivo RNAi technology might be useful for identifying potent but low-penetrance tumor suppressors.
D'Apolito et al. (2002) determined that the mouse Myh9 gene, like human MYH9, contains 41 exons.
By Southern analysis of a panel of human-mouse somatic cell hybrids, Saez et al. (1990) demonstrated that the nonmuscle MHC gene is located on chromosome 22 and is therefore unlinked to the 2 sarcomeric MHC clusters on chromosomes 14 and 17. A cell line containing a translocation involving chromosome 22 allowed a regional assignment to 22pter-q13. Toothaker et al. (1991) mapped the gene to 22q12.3-q13.1 by Southern analysis of human/rodent somatic cell hybrids and by in situ hybridization. Simons et al. (1991) likewise mapped a nonmuscle myosin heavy chain gene, which they designated NMMHCA, to 22q11.2. A second nonmuscle myosin heavy chain, which they designated NMMHC-B (160776), was found to be encoded by a gene on 17q13. Both were 7.5 kb long. In the amino-terminal one-third (amino acids 58-718), they were 89% identical at the amino acid level and 74% identical at the nucleotide level. Muscle myosin heavy chain genes are located on 17p.
D'Apolito et al. (2002) mapped the mouse Myh9 gene to a region of chromosome 15 that shares homology of synteny with human chromosome 22q12.3-q13.1.
Association with Kidney Disease in African Americans
In independent genomewide admixture scans to map susceptibility loci for kidney disease in African Americans, Kopp et al. (2008) and Kao et al. (2008) identified variation at the MYH9 locus as a major factor for the increased risk of nondiabetic kidney disease in this population (FSGS4; 612551).
Macrothrombocytopenia and Granulocyte Inclusions with or without Nephritis or Sensorineural Hearing Loss
Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss (MATINS; 155100) was previously thought to be 4 distinct giant platelet disorders with overlapping features caused by mutation in the MYH9 gene: Fechtner syndrome, May-Hegglin anomaly, Epstein syndrome, and Sebastian syndrome. All 4 were found to represent a single disorder with a continuous clinical spectrum: variable phenotypic expression is observed not only between families but also within families with the same MYH9 mutation (Seri et al., 2003).
The May-Hegglin/Fechtner Syndrome Consortium (2000) identified 6 heterozygous MYH9 mutations in 7 unrelated probands with one or another of 3 giant platelet disorders: May-Hegglin anomaly (R1933X, 160775.0001 and E1841K, 160775.0002), Fechtner syndrome (D1424H, 160775.0005 and R792C, 160775.0006), and Sebastian syndrome (T1155I; 160775.0007). On the basis of molecular modeling, 2 mutations affecting the myosin head domain were predicted to impose electrostatic and conformational changes, whereas the truncating mutation deleted the unique C-terminal tailpiece. The remaining missense mutations, all affecting highly conserved coiled-coil domain positions, imparted destabilizing electrostatic and polar changes. Thus, the findings demonstrated that mutations in MYH9 result in 3 phenotypically distinct megakaryocyte/platelet/leukocyte syndromes and are important in the pathogenesis of sensorineural deafness, cataracts, and nephritis.
Kelley et al. (2000) identified mutations in the MYH9 gene in 10 unrelated patients with May-Hegglin anomaly: E1841K in 5 families, R1933X in 4 families, and T1155I (160775.0007) in the last family.
Kunishima et al. (2001) found mutations in NMMHCA in 6 of 7 Japanese families with macrothrombocytopenia with leukocyte inclusions: 3 missense mutations, 1 nonsense mutation, and a 1-bp deletion resulting in a premature termination. Immunofluorescence studies showed that NMMHCA distribution in neutrophils mimics the inclusion bodies. These results provided evidence for the involvement of an abnormal form of NMMHCA in the creation of leukocyte inclusions and also in platelet morphogenesis.
Heath et al. (2001) examined the spectrum of mutations and the genotype-phenotype and structure-function relationships in a large cohort of 27 individuals with May-Hegglin anomaly, Fechtner syndrome (some cases of which were called Alport-like syndrome with macrothrombocytopenia), or Sebastian syndrome. They found that R702C (160775.0006) and R702H (160775.0009) mutations in the head domain were associated only with Fechtner syndrome (some cases designated as Alport-like syndrome with macrothrombocytopenia) or Epstein syndrome, thus defining a region of the MYHIIA protein critical in the combined pathogenesis of macrothrombocytopenia, nephritis, and deafness. Mutations in the coiled-coil domain (e.g., R1933X; 160775.0001) were common to May-Hegglin anomaly and Fechtner syndrome.
To elucidate the spectrum of MYH9 mutations responsible for the group of disorders under the general designation autosomal dominant macrothrombocytopenia with leukocyte inclusions, Kunishima et al. (2001) examined the MYH9 gene in an additional 11 families and 3 sporadic patients with the disorders from Japan, Korea, and China. All 14 patients had heterozygous MYH9 mutations, including 3 known mutations: R1933X (160775.0001), R1165C (160775.0003), and E1841K (160775.0002). Six novel mutations (3 missense and 3 deletion) were also found. Two patients had Alport manifestations including deafness, nephritis, and cataract and had R1165C and E1841K mutations, respectively. However, taken together with 3 previous reports, the data did not show clear phenotype-genotype relationships.
Hu et al. (2002) noted that 2 disease-causing mutations, N93K (160775.0004) and R702C (160775.0006), lie within close proximity in the 3-dimensional structure of the head domain of MYH9. They coexpressed recombinant fragments of MYH9 along with the appropriate light chains to create 2-headed meromyosin-like molecules bearing these mutations. The R702C mutant displayed 25% of the maximal MgATPase activity of wildtype heavy meromyosin and moved actin filaments at half the wildtype rate in an in vitro motility assay. Heavy meromyosin containing the N93K mutation had only 4% of the maximal MgATPase activity and did not translocate actin filaments. The characteristics of this mutation were consistent with an inability to fully adopt the 'on' conformation. The N93K mutation was also associated with a tendency for the myosin to aggregate, which may explain the leukocyte inclusions associated with this mutation in humans.
In the proband of the family with macrothrombocytopenia and progressive sensorineural deafness reported by Brodie et al. (1992), Mhatre et al. (2003) identified a missense mutation in the MYH9 gene (D1424N; 160775.0010).
Kunishima et al. (2005) identified a mutation (160775.0011) in a 1-year-old boy with May-Hegglin anomaly resulting from somatic mosaicism in the father.
By immunofluorescence analysis using a polyclonal antibody against human platelet MYH9, Kunishima et al. (2003) detected abnormal subcellular localization of MYH9 in neutrophils from all 21 patients with MYH9 mutations examined, including a patient with Epstein syndrome. Comparison with May-Grunwald-Giemsa staining revealed that the antibody always coexisted with the neutrophil inclusion bodies, providing proof that MYH9 is associated with such bodies. In some cases, neutrophil inclusions were not detected on conventional May-Grunwald-Giemsa-stained blood smears, but immunofluorescence analysis found the abnormal MYH9 localization. Kunishima et al. (2003) proposed that the mutant MYH9 protein dimerizes with the wildtype protein to form inclusions, consistent with a dominant-negative effect.
Pecci et al. (2005) investigated 11 patients from 6 pedigrees with different MYH9 mutations (see, e.g., 160775.0001-160775.0005). NMHC IIA levels were measured in platelets and granulocytes isolated from peripheral blood and in megakaryocytes cultured from circulating progenitors. All patients studied had a 50% reduction of NMHC IIA expression in platelets and megakaryocytes. In subjects with the R1933X (160775.0001) and E1945X mutations, the whole NMHC IIA of platelets and megakaryocytes was wildtype. No NMHC IIA inclusions were observed at any time of megakaryocyte maturation. In granulocytes, the extent of NMHC IIA reduction in patients with respect to control cells was significantly greater than that measured in platelets and megakaryocytes; wildtype protein was sequestered within most of the NMHC IIA inclusions. These results indicated that haploinsufficiency of NMHC IIA in megakaryocytic lineage is the mechanism of macrothrombocytopenia consequent to MYH9 mutations, whereas in granulocytes a dominant-negative effect of the mutant allele appeared to be involved in the formation of inclusion bodies.
Balduini et al. (2011) noted that at least 44 different mutations had been identified in 218 unrelated families with MATINS. Of these, 27 are amino acid substitutions affecting 19 of the 1,960 residues of the protein. In 79% of patients, mutations affect only 6 residues: ser96 (6%) and arg702 (24%) in the globular head, arg1165 (9%), asp1424 (20%), and glu1842 (22%) in the coiled-coil domain, or arg1933 (19%) in the nonhelical portion of the tail domain.
Deafness, Autosomal Dominant 17
Lalwani et al. (2000) demonstrated heterozygosity for a missense mutation (R705H; 160775.0008) in the MYH9 gene in affected members of a kindred with deafness (DFNA17; 603622).
Hildebrand et al. (2006) reported a 5-generation Australian family of Anglo Celtic origin with nonsyndromic DFNA17 caused by heterozygosity for the R705H mutation.
In a Brazilian family in which 10 members had nonsyndromic hearing loss at all frequencies, Dantas et al. (2014) identified heterozygosity for the same R705H mutation in the MYH9 gene. The mutation segregated with the phenotype in the family.
From a study of 13 families with macrothrombocytopenia and granulocyte inclusions with or without nephropathy or hearing loss and a review of the literature, Dong et al. (2005) suggested that mutation in the C-terminal coiled-coil region or truncation of the tailpiece of the MYH9 gene is associated with a hematologic-only phenotype, whereas mutation of the head ATPase domain is more frequently associated with the additional features of nephropathy and hearing loss.
In a study of 108 patients from 50 unrelated pedigrees with MYH9 mutations, Pecci et al. (2008) found that 68% of families carried mutations in 1 of 4 residues: 702 in the motor domain (12 families) and residues 1424, 1841, and 1933 in the tail domain (9, 7, and 6 pedigrees, respectively). All subjects with mutations in the motor domain of MYH9 developed severe thrombocytopenia, nephritis, and deafness before the age of 40 years. Patients with mutations at residue 1424 or 1841 had a much lower risk of these complications, significantly higher platelet counts, and an intermediate clinical picture. Patients with mutations at residue 1933 did not develop kidney damage or cataracts but did develop deafness late in life.
Matsushita et al. (2004) found that homozygous deletion of Myh9 in mice was embryonic lethal. In contrast, Myh9 +/- mice were viable and fertile without gross anatomic, hematologic, or nephrologic abnormalities. However, auditory brainstem responses indicated that 2 of 6 Myh9 +/- mice had hearing loss. Parker et al. (2006) also found that homozygous mutations in Myh9 are embryonic lethal in mice. In contrast to the findings of Matsushita et al. (2004), Parker et al. (2006) did not observe hearing loss in Myh9 heterozygous adult mice, despite haploinsufficiency for Myh9 in the mutant mouse inner ear. In addition, aged Myh9 heterozygous mice did not show signs of cochleosaccular degeneration common in DFNA17. Parker et al. (2006) used a public gene-targeted embryonic stem cell bank resource to generate the mice.
Seri et al. (2002) suggested that the R702C (160775.0006) mutation is associated with Fechtner syndrome, in which inclusion bodies are found in the leukocytes. Such bodies were said to be absent in Epstein syndrome, and Seri et al. (2002) suggested, on the basis of predictions from molecular modeling of the x-ray crystallographic structure of chick smooth muscle myosin, that the mutated thiol-reactive group of R702C might lead to intermolecular disulfide bridges, with the consequent formation of inclusions typical of Fechtner syndrome. On the contrary, the R702H mutation, they suggested, does not allow the protein to aggregate and thus to generate 'Dohle-like' bodies. It should be pointed out, however, that the kindred (family F) originally described by Epstein et al. (1972) carried the R702C mutation.
In a family used in linkage studies to define the May-Hegglin anomaly (MATINS; 155100) critical region on chromosome 22 (Martignetti et al., 2000), the May-Hegglin/Fechtner Syndrome Consortium (2000) found that affected individuals had a heterozygous nonsense mutation in codon 1933 of the MYH9 gene, predicting the replacement of an arginine by a stop codon (R1933X) and deletion of the last 28 amino acids.
Kelley et al. (2000) found the R1933X mutation in 4 of 10 families they studied with May-Hegglin anomaly. It was caused by a 5797C-T transition in exon 40.
Heath et al. (2001) identified a heterozygous R1933X mutation in affected members of a family described as having Fechtner syndrome, although deafness and cataract were not present. Another family with the R1933X mutation was described as having May-Hegglin anomaly/Sebastian syndrome.
Rabbolini et al. (2018) reported 2 Australian patients with macrothrombocytopenia and granulocyte inclusions who were heterozygous for the R1933X mutation; one of the patients also had renal impairment.
In 2 unrelated families with May-Hegglin anomaly (MATINS; 155100), the May-Hegglin/Fechtner Syndrome Consortium (2000) found that affected individuals had the same missense mutation, glu1841 to lys (E1841K), within the coiled-coil domain of the MYH9 protein. The missense mutation was caused by a G-to-A transition at nucleotide 5521 in exon 38. Neither family history nor haplotype analysis suggested common ancestry.
Kelley et al. (2000) found the E1841K mutation in 5 of 10 families studied with May-Hegglin anomaly and commented that it occurs at a conserved site in the rod domain.
Heath et al. (2001) identified a heterozygous E1841K mutation in 2 unrelated families with Fechtner syndrome. One of the families had been reported by Rocca et al. (1993); in this 4-generation family, only some affected members had 'Alport-like' symptoms, such as deafness, nephritis, and cataracts, consistent with 'reduced expression of Alport manifestations.'
In a family diagnosed with Sebastian syndrome (MATINS; 155100), the May-Hegglin/Fechtner Syndrome Consortium (2000) found that affected individuals had a heterozygous 3493C-T transition in the MYH9 gene, resulting in an arg1165-to-cys (R1165C) substitution.
In a family with May-Hegglin anomaly (MATINS; 155100), the May-Hegglin/Fechtner Syndrome Consortium (2000) found that the proband had a heterozygous 279C-G transversion in the MYH9 gene, resulting in an asn93-to-lys (N93K) substitution within the globular head domain.
In a family with Fechtner syndrome (MATINS; 155100) that had been used to define the critical Fechtner syndrome mapping region (Cusano et al., 2000), the May-Hegglin/Fechtner Syndrome Consortium (2000) found that all affected individuals had a missense mutation in codon 1424 (asp1424 to his; D1424H) within the coiled-coil domain of the MYH9 protein. The mutation resulted from a G-to-C transversion at nucleotide 4270.
The May-Hegglin/Fechtner Syndrome Consortium (2000) found that a sporadic case of Fechtner syndrome (MATINS; 155100) (Moxey-Mims et al., 1999) had a missense mutation in codon 702 (arg702 to cys; R702C) of the MYH9 protein, altering the globular head domain. The mutation, which resulted from a C-to-T transition at nucleotide 2104, was not present in either ascertained parent.
In 1 of the original families (family F) with Epstein syndrome described by Epstein et al. (1972), Heath et al. (2001) found a transition in exon 16 of the MYH9 gene converting codon 702 from CGT (arg) to TGT (cys). Heath et al. (2001) found that the R702C mutation was one of the most frequent, being found in 6 of the 20 families in which they identified a specific mutation. All of the families represented Fechtner syndrome. There was no mention of leukocyte inclusions in the original work-up of this family. For logistic reasons it had been impossible to get a more recent blood sample for checking (Epstein, 2002).
Seri et al. (2003) identified a heterozygous R702C mutation in a patient with sporadic Fechtner syndrome, 2 unrelated patients with sporadic Epstein syndrome, a patient with sporadic May-Hegglin anomaly, and in affected members of a family with May-Hegglin anomaly and Sebastian syndrome.
Kelley et al. (2000) observed a family in which mother and daughter had May-Hegglin anomaly (MATINS; 155100) caused by a thr1155-to-ile (T1155I) mutation in the MYH9 gene resulting from a C-to-T transition at nucleotide 3464. The mutation was not present in the mother's parents, thus representing a new mutation. Kelley et al. (2000) commented that the T1155I mutation occurs at a conserved site in the rod domain.
In 2 affected individuals from a family with Fechtner syndrome, Seri et al. (2003) identified a heterozygous T1155I mutation. Seri et al. (2003) concluded that May-Hegglin anomaly and Fechtner syndrome are not distinct entities, but rather represent a single disease with a continuous clinical spectrum. The common abnormality is macrothrombocytopenia and abnormal distribution of MYH9 within leukocytes, even in those without classic Dohle bodies.
In affected members of a 5-generation family with autosomal dominant deafness characterized by progressive hearing impairment and cochleosaccular degeneration (DFNA17; 603622) previously described by Lalwani et al. (1997), Lalwani et al. (2000) found a G-to-A transition at nucleotide 2114 in the MYH9 gene. This missense mutation changed codon 705 from an invariant arginine to a histidine within a highly conserved SH1 linker region. Previous studies had shown that modification of amino acid residues within the SH1 helix causes dysfunction of the ATPase activity of the motor domain in myosin II.
Hildebrand et al. (2006) reported a 5-generation Australian family of Anglo Celtic origin with nonsyndromic DFNA17 due to a heterozygous R705H mutation. The self-reported age of onset ranged from 6 years to the mid-twenties. The hearing loss became severe to profound by the second to third decades, although there was some intrafamilial variability. Five affected individuals received cochlear implants with excellent results. Hildebrand et al. (2006) noted the contrast between the results of cochlear implant in this family and the poor results reported in 1 patient from the family of Lalwani et al. (2000). Hildebrand et al. (2006) speculated that early intervention plays an important role in the therapeutic response.
In a Brazilian family in which 10 members had nonsyndromic hearing loss at all frequencies, Dantas et al. (2014) identified heterozygosity for the same R705H mutation in the MYH9 gene. The mutation segregated with the phenotype in the family. Three other members of the family with hearing loss at high frequencies did not have the mutation.
Verver et al. (2015) identified the R705H mutation in MYH9 in 2 unrelated families whose 4 affected individuals had not only hearing impairment, but also what the authors reported as thrombocytopenia, giant platelets, leukocyte inclusions, and mild to moderate elevation of some liver enzymes. They argued that DFNA17 should not be considered a separate genetic entity; however, the 4 affected individuals had platelet counts ranging from 96,000 to 142,000 and 2 had easy bruising, but none had spontaneous bleeding. While liver enzyme elevation was reported, the involvement was defined as ratios of ALT, AST, and GGT with respect to the upper limit of normal. All 4 patients had leukocyte inclusions. Mean platelet diameter varied between 3.8 and 4.5 microns, which is above the upper limit of normal range of 2.6.
In a European family living in the United States with Fechtner syndrome (MATINS; 155100), Heath et al. (2001) found a transition converting codon 702 from CGT (arg) to CAT (his). The globular head domain of the MYHIIA protein was affected.
Seri et al. (2002) identified the same R702H mutation in affected members of 2 families, 1 Finnish and 1 Italian, with the phenotype they labeled Epstein syndrome. In the Finnish family, a 22-year-old man and his son were affected. The father had had recurrent nose bleeding from the age of 2 years. The Italian family had 6 affected members in 4 sibships in 3 generations. The proposita was a 35-year-old woman who had been known to be thrombocytopenic, with mild bleeding diathesis, from the age of 7 years. Hearing loss was selective for high tones. No renal problem was mentioned. Her father, however, had required hemodialysis from the age of 28 years and died at the age of 44 from end-stage kidney failure.
Deutsch et al. (2003) studied a Swiss family and an American family with the May-Hegglin anomaly/Fechtner syndrome (MATINS; 155100) and found an asp1424-to-asn (D1424N) mutation in the MYH9 gene. Affected members in both families presented with severe thrombocytopenia, as well as characteristic giant platelets and Dohle-like inclusion bodies on blood smear examination. In the Swiss family, 2 affected sisters developed bilateral cataracts at a young age, whereas the third sister and her son had high-tone sensorineural deafness. Two individuals with thrombocytopenia showed no extrahematologic symptoms. None showed signs of nephritis. In the American family, 4 individuals suffered from sensorineural deafness, but no cataracts or nephritis were observed. Haplotype analysis indicated that in this family the mutation was a de novo event in 1 individual. The same mutation had previously been described in a pedigree of Japanese origin and in 2 pedigrees of American origin, most likely as a result of independent mutation events (Heath et al., 2001; Kunishima et al., 2001). Deutsch et al. (2003) demonstrated that the phenotypes result from a highly unstable MYH9 protein. No abnormalities in protein localization or mRNA stability were observed. They hypothesized that haploinsufficiency of MYH9 results in a failure to properly reorganize the cytoskeleton in megakaryocytes as required for efficient platelet production.
In the proband of the family with macrothrombocytopenia and progressive sensorineural deafness reported by Brodie et al. (1992), Mhatre et al. (2003) identified a heterozygous 4270G-A transition in exon 30 of the MYH9 gene, resulting in the D1424N substitution in the highly conserved coiled-coil region of the protein.
Seri et al. (2003) identified a heterozygous D1424N mutation in a patient described as having May-Hegglin anomaly and Sebastian syndrome. The authors suggested that the 2 disorders are not separate entities, but rather represent the same disease with a continuous clinical spectrum.
Kunishima et al. (2005) found a 1-bp deletion, 5818delG, in the MYH9 gene as the cause of May-Hegglin anomaly (MATINS; 155100) in a 1-year-old boy. The deletion resulted in frameshift and premature termination. Kunishima et al. (2005) found that the father was a somatic mosaic for this mutation. The father had normal platelet counts; however, both normal-sized and giant platelets were observed on his peripheral blood smears. In addition, 14% of neutrophils contained inclusion bodies, and the rest showed a normal morphology. Quantitative fluorescent PCR analysis showed that only 6% of DNA from peripheral blood leukocytes harbored the mutation. The mutation was demonstrated in a similar frequency in different tissues, buccal mucosa cells, and hair bulb cells, implying that the mutation had occurred during gastrulation. Kunishima et al. (2005) concluded that mosaicism may account for some de novo mutations in MYH9 disorders.
In affected individuals from 2 unrelated families with Epstein syndrome (MATINS; 155100), Arrondel et al. (2002) identified a heterozygous 287C-T transition in the MYH9 gene, resulting in a ser96-to-leu (S96L) substitution predicted to disturb the helical region of the protein.
Utsch et al. (2006) identified a de novo heterozygous S96L mutation in an infant girl with features of Epstein syndrome, including macrothrombocytopenia and impaired platelet function but no evidence of hearing loss or nephritis. She also had exstrophy of the bladder (600057). Utsch et al. (2006) noted that although MYH9 mutations had not previously been associated with urogenital malformations, the mutation may have played a role in the bladder exstrophy in this patient.
By immunofluorescence studies of leukocytes derived from a patient with the S96L mutation, Kunishima et al. (2003) detected abnormal subcellular localization of MYH9, showing a speckled pattern or small dots. Neutrophil inclusions had not been found on conventional Giemsa staining.
In a patient described as having May-Hegglin anomaly and Sebastian syndrome (MATINS; 155100), Seri et al. (2003) identified a heterozygous 21-bp deletion in the MYH9 gene, resulting in an in-frame deletion of 7 amino acids (E1066-A1072) in the rod domain. De Rocco et al. (2009) identified the reciprocal in-frame duplication in another family (160775.0014). Detailed sequence analysis of this region revealed a 16-nucleotide repeat that was likely responsible for unequal crossing-over.
In 3 affected members of a family with May-Hegglin anomaly (MATINS; 155100), De Rocco et al. (2009) identified a heterozygous 21-bp duplication in exon 24 of the MYH9 gene, resulting in an in-frame duplication of 7 amino acids (E1066-A1072) in the rod domain. All patients had congenital macrothrombocytopenia and Dohle-like inclusion bodies in neutrophils, consistent with May-Hegglin anomaly, and 1 patient also had congenital cataracts, which is part of the phenotypic spectrum of MYH9-related disorders. Seri et al. (2003) identified the reciprocal in-frame deletion in another patient (160775.0013). Detailed sequence analysis of this region revealed a 16-nucleotide repeat that was likely responsible for unequal crossing-over.
In a 45-year-old Japanese man with macrothrombocytopenia and sensorineural deafness (MATINS; 155100), Kunishima et al. (2005) identified a heterozygous 18-bp deletion (228_245del) in exon 1 of the MYH9 gene, resulting in an in-frame deletion of 6 amino acids (asn76 to ser81) in a helix segment adjacent to the SH1 helix. The mutation affected the N-terminal head domain. The patient had no evidence of renal dysfunction or cataract. Leukocyte morphology on conventional Giemsa staining was ambiguous, but immunofluorescence staining showed abnormal subcellular localization of MYH9. The MYH9-positive structures showed a thread-like appearance, not punctuated or granular as often described in other MYH9-related disorders.
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