HGNC Approved Gene Symbol: LZTR1
Cytogenetic location: 22q11.21 Genomic coordinates (GRCh38): 22:20,982,297-20,999,032 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q11.21 | {Schwannomatosis-2, susceptibility to} | 615670 | Autosomal dominant | 3 |
| Noonan syndrome 10 | 616564 | Autosomal dominant | 3 | |
| Noonan syndrome 2 | 605275 | Autosomal recessive | 3 |
The LZTR1 gene encodes a protein that belongs to a functionally diverse superfamily of BTB/POZ (broad complex, tramtrack, and bric-a-brac/poxvirus and zinc finger) proteins. BTB-containing proteins control fundamental cellular processes, ranging from the regulation of chromatin conformation to the cell cycle (summary by Piotrowski et al., 2014).
By a microdissection and microcloning method, Kurahashi et al. (1995) constructed a specific plasmid library from the 22q11 region which is commonly deleted in the DiGeorge syndrome (DGS; 188400). Dosage analysis proved that 3 of 144 randomly selected microclones detected hemizygosity in 2 patients with DGS. They then obtained 2 cosmid contigs corresponding to the microclones and using 1 of the cosmids of 1 of the contigs identified a 4.3-kb cDNA from a fetal brain cDNA library. Sequence analysis of the cDNA revealed an open reading frame encoding 552 amino acids that had several characteristics of DNA-binding proteins. The gene, designated LZTR1 (for leucine-zipper-like transcriptional regulator-1) by them, was transcribed in several essential fetal organs and proved to be hemizygously deleted in 7 of 8 DGS patients or its variants. Although LZTR1 did not locate in the shortest region of overlap of DGS, several of its structural characteristics identified it as a transcriptional regulator, suggesting that it plays a crucial role in embryogenesis and that haploinsufficiency of this gene may be partly responsible for the developmental abnormalities of DGS.
Using immunoprecipitation of endogenous LZTR1 followed by Western blotting, Umeki et al. (2019) showed that LZTR1 bound to the RAF1 (164760)-SHOC2 (602775)-PPP1CB (600590) complex. Mutations in these genes cause Noonan syndrome or Noonan-like phenotypes. Cells transfected with siRNA against LZTR1 exhibited decreased levels of RAF1 phosphorylated at ser259.
By trapping LZTR1 complexes from intact mammalian cells, Steklov et al. (2018) identified the guanosine triphosphatase RAS (see 190020) as a substrate for the LZTR1-CUL3 complex. Ubiquitome analysis showed that loss of Lztr1 abrogated Ras ubiquitination at lysine-170. LZTR1-mediated ubiquitination inhibited RAS signaling by attenuating its association with the membrane.
Bigenzahn et al. (2018) found that knockdown of the Drosophila LZTR1 ortholog CG3711 resulted in a Ras-dependent gain-of-function phenotype. Endogenous human LZTR1 associates with the main RAS isoforms. Inactivation of LZTR1 led to decreased ubiquitination and enhanced plasma membrane localization of endogenous KRAS (190070). Bigenzahn et al. (2018) proposed that LZTR1 acts as a conserved regulator of RAS ubiquitination and MAPK pathway activation. LZTR1 disease mutations failed to revert loss-of-function phenotypes.
The LZTR1 gene maps to chromosome 22q11 (Kurahashi et al., 1995).
Schwannomatosis 2
In 16 of 20 probands with schwannomatosis-2 (SWN2; 615670), Piotrowski et al. (2014) identified 15 different germline heterozygous mutations in the LZTR1 gene (see, e.g., 600574.0001-600574.0006). There were 6 truncating mutations, 1 in-frame splice site mutation, 1 deletion affecting a splice site, and 7 missense mutations at highly conserved residues. All schwannomas studied also carried the heterozygous LZTR1 mutation, and all showed loss of heterozygosity (LOH) at chromosome 22q11, including the LZTR1, SMARCB1 (601607), and NF2 (607379) genes. In addition, all tumors from all patients carried a heterozygous somatic mutation in the NF2 gene. These findings were consistent with biallelic loss of function of both LZTR1 and NF2 in all tumors. Functional studies of the variants were not performed. Piotrowski et al. (2014) characterized the pathogenesis of tumor development as resulting from 3 mutational events: a germline LZTR1 mutation (E1), a deletion of 22q that includes the LZTR1 and NF2 genes (E2), and a somatic NF2 mutation (E3). None of the patients or tumors carried a SMARCB1 mutation. The germline mutations segregated with the disorder in all available affected first-degree relatives, although 4 asymptomatic parents also carried the mutation, indicating incomplete penetrance. The findings suggested that loss of LZTR1 function can predispose to the development of autosomal dominant multiple schwannomas, thus implicating LZTR1 as a tumor suppressor gene.
Noonan Syndrome 10
In affected members of 5 families with Noonan syndrome-10 (NS10; 616564), Yamamoto et al. (2015) identified 5 different heterozygous missense mutations in the LZTR1 gene (see, e.g., 600574.0007-600574.0009). All of the mutations occurred in the Kelch (KT) domains, but functional studies of the variants were not performed. Mutations in 4 of the families were found by whole-exome sequencing of a cohort of 50 Brazilian patients with Noonan syndrome; the fifth family was of Polish origin.
Umeki et al. (2019) reported 6 NS10 patients with heterozygous mutations in LZTR1. All patients had cardiac defects; other features were more variable.
Noonan Syndrome 2
Johnston et al. (2018) reported 17 mutations in 12 families with autosomal recessive Noonan syndrome (NS2; 605275). These included missense, nonsense, frameshift, and splice site mutations that occurred in homozygosity or compound heterozygosity. All parents were heterozygous and unaffected.
Umeki et al. (2019) reported 1 NS2 patient with compound heterozygous mutations in the LZTR1 gene as well as 6 NS10 patients with heterozygous mutations in LZTR1. All patients had cardiac defects and 71%, including the NS2 patient, had hypertrophic cardiomyopathy. Other features were more variable. The patient with NS2 inherited each mutation from one of her unaffected parents.
Functional Studies of LZTR1 Mutations
Using transfected COS-1 and HEK293T cells, Motta et al. (2019) found that the NS-causing dominant mutations in LZTR1 did not impact protein stability or Golgi localization, but they enhanced stimulus-dependent RAS-MAPK signaling. In contrast, NS-causing recessive mutations in LZTR1 caused loss of function by affecting either protein stability or Golgi localization, but they had no impact on RAS-MAPK signaling. Coimmunoprecipitation analysis showed that NS-causing dominant mutations in LZTR1 did not affect BTB domain-mediated binding to CUL3 (603136). Structural analysis suggested that NS-causing dominant mutations in LZTR1 affected the substrate-binding Kelch domain of LZTR1, which mediates binding of substrate to the CUL3-RING ubiquitin ligase complex to promote substrate ubiquitination.
Steklov et al. (2018) found that LZTR1 haploinsufficiency in mice recapitulated Noonan syndrome phenotypes, whereas LZTR1 loss in Schwann cells drove differentiation and proliferation. Loss of Lztr1 was lethal between embryonic day embryonic day 17.5 and birth. Lztr1 +/- male mice exhibited decreased weight and facial dysmorphia. Lztr1 +/- mice, both male and female, displayed heart malformations, including decreased left ventricular systolic function, increased diastolic dimensions, eccentric hypertrophy, increased cardiomyocyte area, and reduced longevity.
Castel et al. (2019) used an isogenic germline knockin mouse model to study the effects of RIT1 (609591) mutation at the organismal level, which resulted in a phenotype resembling Noonan syndrome. By mass spectrometry, Castel et al. (2019) detected a RIT1 interactor, LZTR1, that acts as an adaptor for protein degradation. Pathogenic mutations affecting either RIT1 or LZTR1 resulted in incomplete degradation of RIT1. This led to RIT1 accumulation and dysregulated growth factor signaling responses. Castel et al. (2019) concluded that their results highlighted a mechanism of pathogenesis that relies on impaired protein degradation of the Ras GTPase RIT1.
In a father and 2 of his adult children with schwannomatosis-2 (SWN2; 615670), Piotrowski et al. (2014) identified a germline heterozygous G-to-A transition in intron 2 of the LZTR1 gene (c.264-13G-A), predicted to result in premature termination (Lys89CysfsTer16) and a loss of function. The mutation was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project databases. Tumor tissue also carried the heterozygous LZTR1 mutation, and showed loss of heterozygosity (LOH) at chromosome 22q11, including both the LZTR1 and NF2 (607379) genes. In addition, the tumors carried a heterozygous somatic mutation in the NF2 gene. These findings were consistent with biallelic loss of function of both LZTR1 and NF2 in all tumors.
In a father and son with schwannomatosis-2 (SWN2; 615670), Piotrowski et al. (2014) identified a germline heterozygous c.365C-T transition in exon 4 of the LZTR1 gene, resulting in a ser122-to-leu (S122L) substitution at a highly conserved residue in the second Kelch motif. The mutation was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project databases. Functional studies of the variant were not performed. Tumor tissue also carried the heterozygous LZTR1 mutation, and showed loss of heterozygosity (LOH) at chromosome 22q11, including both the LZTR1 and NF2 (607379) genes. In addition, the tumors carried a heterozygous somatic mutation in the NF2 gene. These findings were consistent with biallelic loss of function of both LZTR1 and NF2 in all tumors.
Steklov et al. (2018) found that LZTR1 Kelch domain mutants, including S122L, showed decreased binding to RAS in coimmunoprecipitation assays.
In a woman with schwannomatosis-2 (SWN2; 615670), Piotrowski et al. (2014) identified a germline heterozygous c.2062C-T transition in exon 17 of the LZTR1 gene, resulting in an arg688-to-cys (R688C) substitution at a highly conserved residue in the BTB-II domain. The patient's unaffected father also carried this mutation, indicating incomplete penetrance. An unrelated 34-year-old woman with apparently sporadic disease also carried this mutation. The mutation was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project databases. Tumor tissue also carried the heterozygous LZTR1 mutation, and showed loss of heterozygosity (LOH) at chromosome 22q11, including both the LZTR1 and NF2 (607379) genes. In addition, the tumors carried a heterozygous somatic mutation in the NF2 gene. These findings were consistent with biallelic loss of function of both LZTR1 and NF2 in all tumors.
Steklov et al. (2018) found that R688C LZTR1 protein exhibited reduced binding to CUL3. On immunostaining, mutant protein showed diffuse cytoplasmic localization rather than the punctate endomembrane localization displayed by wildtype.
In a woman with schwannomatosis-2 (SWN2; 615670), Piotrowski et al. (2014) identified a germline heterozygous 1-bp deletion (27delG) in exon 1 of the LZTR1 gene, resulting in a frameshift and premature termination (Gln10ArgfsTer15). The mutation was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project databases. Tumor tissue also carried the heterozygous LZTR1 mutation, and showed loss of heterozygosity (LOH) at chromosome 22q11, including both the LZTR1 and NF2 (607379) genes. In addition, the tumors carried a heterozygous somatic mutation in the NF2 gene. These findings were consistent with biallelic loss of function of both LZTR1 and NF2 in all tumors.
In a father and 2 of his adult children with schwannomatosis-2 (SWN2; 615670), Piotrowski et al. (2014) identified a germline heterozygous 4-bp deletion (c.2348_2351delCGCA) in exon 20 of the LZTR1 gene, resulting in a frameshift and premature termination (Thr783ArgfsTer5). The mutation was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project databases. Tumor tissue also carried the heterozygous LZTR1 mutation, and showed loss of heterozygosity (LOH) at chromosome 22q11, including both the LZTR1 and NF2 (607379) genes. In addition, the tumors carried a heterozygous somatic mutation in the NF2 gene. These findings were consistent with biallelic loss of function of both LZTR1 and NF2 in all tumors.
In a father and his adult daughter with schwannomatosis-2 (SWN2; 615670), Piotrowski et al. (2014) identified a germline heterozygous c.1397G-A transition in exon 13 of the LZTR1 gene, resulting in an arg466-to-gln (R466Q) substitution at a highly conserved residue in the BTB-I domain. The mutation was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project databases. Functional studies of the variant were not performed. Tumor tissue also carried the heterozygous LZTR1 mutation, and showed loss of heterozygosity (LOH) at chromosome 22q11, including both the LZTR1 and NF2 (607379) genes. In addition, the tumors carried a heterozygous somatic mutation in the NF2 gene. These findings were consistent with biallelic loss of function of both LZTR1 and NF2 in all tumors.
Steklov et al. (2018) found that R466Q LZTR1 protein exhibited reduced binding to CUL3. On immunostaining, mutant protein showed diffuse cytoplasmic localization rather than the punctate endomembrane localization displayed by wildtype.
In 6 members of a Brazilian family (Br-F4) with Noonan syndrome-10 (NS10; 616564), Yamamoto et al. (2015) identified a heterozygous c.850C-T transition (c.850C-T, NM_006767.3) in exon 9 of the LZTR1 gene, resulting in an arg284-to-cys (R284C) substitution in the KT4 domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the 1000 Genomes Project and Exome Sequencing Project databases and 609 Brazilian controls. Functional studies of the variant were not performed.
Jacquinet et al. (2020) reported a 26-year-old male with NS10 who had inherited the R284C mutation from his affected mother. He developed an oligoastrocytoma at age 22 years that was resected but recurred as a ganglioblastoma at age 26 years. The patient had been treated with growth hormone for short stature between ages 15 and 17 years. Facial features of Noonan syndrome, kyphoscoliosis with gibbus, and pectus excavatum were present; cardiac malformation, cardiomyopathy, and hyperkeratosis were absent. Jacquinet et al. (2020) hypothesized that gliomas are a possible complication of LZTR1-related Noonan syndrome, and stated that their report supported a possible link between occurrence of a cerebral tumor in Noonan syndrome and treatment with growth hormone. In addition to the R284C mutation, the patient and his mother carried a mutation resulting in Charcot-Marie-Tooth disease type 1A (CMT1A; 601097).
In 3 members of a Brazilian family (Br-F3) with Noonan syndrome-10 (NS10; 616564), Yamamoto et al. (2015) identified a heterozygous c.742G-A transition (c.742G-A, NM_006767.3) in exon 8 of the LZTR1 gene, resulting in a gly248-to-arg (G248R) substitution in the KT4 domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the 1000 Genomes Project and Exome Sequencing Project databases and 609 Brazilian controls. Functional studies of the variant were not performed.
Steklov et al. (2018) found that LZTR1 Kelch domain mutants, including G248R, showed decreased binding to RAS in coimmunoprecipitation assays.
In a Polish mother and son (family Po-F1) with Noonan syndrome-10 (NS10; 616564), Yamamoto et al. (2015) identified a heterozygous c.740G-A transition (c.740G-A, NM_006767.3) in exon 8 of the LZTR1 gene, resulting in a ser247-to-asn (S247N) substitution in the KT4 domain. Functional studies of the variant were not performed. The mother developed multiple schwannomas in her right arm, suggesting that the mutation resulted in a loss of function, as observed in schwannomatosis-2 (SWN2; 615670).
In a nonconsanguineous family of European origin (family 1) with 4 affected sibs with autosomal recessive Noonan syndrome (NS2; 605275), Johnston et al. (2018) reported compound heterozygosity for mutations in the LZTR1 gene: a paternally inherited C-to-T transition at nucleotide 628 (c.628C-T, NM_006767.3), resulting in substitution of a premature termination codon for arg210 (R210X), and a maternally inherited splice site mutation (c.2220-17C-A; 600574.0011). Parents had no dysmorphic features of Noonan syndrome. One affected sib developed acute lymphoblastic leukemia at age 5 years, which progressed to acute myeloblastic leukemia at 7 years and resulted in death at age 9 years. Several family members had subtle imaging findings consistent with schwannomas. The R210X mutation was seen in 21 of 281,548 alleles in gnomAD, never in homozygosity (Hamosh, 2018). The splice site mutation produced a splice variant that retained intron 18, which predicted premature termination (Tyr741HisfsTer89). Sanger sequencing of a SNP in the LZTR1 gene showed cDNA skewing toward this transcript, suggesting moderate nonsense-mediated decay of the R210X-mutated transcript. The c.2220-17C-A mutation was seen in 2 of 281,760 alleles in gnomAD, never in homozygosity (December 14, 2018) (Hamosh, 2018).
For discussion of the c.2220-17C-A mutation (c.2220-17C-A, NM_006767.3) in the LZTR1 gene, resulting in retention of intron 18, frameshift, and premature termination of the protein, that was found in compound heterozygous state in 4 sibs with autosomal recessive Noonan syndrome (NS2; 605275) by Johnston et al. (2018), see 600574.0010.
In affected members of 4 families (2, 3, 10, and 11) with autosomal recessive Noonan syndrome (NS2; 605275), Johnston et al. (2018) identified a splice site mutation (c.1943-256C-T, NM_006767.3) in the LZTR1 gene. The mutation occurred 3 times in heterozygosity and once in homozygosity. RT-PCR data from lymphoblasts showed the c.1943-256C-T mutation caused retention of a 117-bp alternate exon that lies within intron 16 of LZTR1. The c.1943-256C-T mutation was seen in 11 of 178,598 alleles in gnomAD, never in homozygosity (December 14, 2018) (Hamosh, 2018).
In the proband of a family (7) with Noonan syndrome-2 (NS2; 605275), Johnston et al. (2018) identified compound heterozygosity for 2 missense mutations in the LZTR1 gene: the maternal allele carried a G-to-A transition at nucleotide 2264 (c.2264G-A, NM_006767.3) resulting in an arg-to-gln substitution at codon 755 (R755Q), and the paternal allele carried a C-to-G transversion at nucleotide 361 that resulted in a his121-to-asp (H121D) substitution. The proband had increased nuchal translucency prenatally, and his brother was born at 28 weeks' gestation with hydrops fetalis and died neonatally. Johnston et al. (2018) reported that the H121D variant was not seen in gnomAD, and that the R755Q variant occurred in 1 of 246,052 alleles.
For discussion of the c.361C-G transversion (c.361C-G, NM_006767.3) in the ZTR1 gene, resulting in a his121-to-asp (H121D) substitution, that was found in compound heterozygous state in a proband with autosomal recessive Noonan syndrome (NS2; 605275) by Johnston et al. (2018), see 600574.0013.
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