Methylthioadenosine phosphorylase (<i>MTAP</i>) in hearing: Gene disruption by chromosomal rearrangement in a hearing impaired individual and model organism analysis

Williamson, Robin E.; Darrow, Keith N.; Michaud, Sébastien; Jacobs, Julie S.; Jones, Marilyn C.; Eberl, Daniel F.; Maas, Richard L.; Liberman, M. Charles

doi:10.1002/ajmg.a.31724

Cited by 12 publications

(8 citation statements)

References 36 publications

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“…Early embryonic lethality in mice homozygous for null mutations has been observed for several mouse tumor suppressor genes including Rb , Wt1 , Apc , Nf2 and Brca1 (30). Our findings are also consistent with those published by (31), which also found that Mtap was an essential gene in mice.…”

Section: Discussionsupporting

confidence: 94%

Mice Heterozygous for Germ-line Mutations in Methylthioadenosine Phosphorylase (MTAP) Die Prematurely of T-Cell Lymphoma

Kadariya¹,

Yin

Tang³

et al. 2009

Cancer Research

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Large homozygous deletions of 9p21 that inactivate CDKN2A, ARF, and MTAP are common in a wide variety of human cancers. The role for CDKN2A and ARF in tumorigenesis is well established, but whether MTAP loss directly affects tumorigenesis is unclear. MTAP encodes the enzyme methylthioadenosine phosphorylase, a key enzyme in the methionine salvage pathway. To determine if loss of MTAP plays a functional role in tumorigenesis, we have created an MTAP-knockout mouse. Mice homozygous for a MTAP null allele (Mtap lacZ ) have an embryonic lethal phenotype dying around day 8 postconception. Mtap/Mtap lacZ heterozygotes are born at Mendelian frequencies and appear indistinguishable from wild-type mice during the first year of life, but they tend to die prematurely with a median survival of 585 days. Autopsies on these animals reveal that they have greatly enlarged spleens, altered thymic histology, and lymphocytic infiltration of their livers, consistent with lymphoma. Immunohistochemical staining and fluorescence-activated cell sorting analysis indicate that these lymphomas are primarily T-cell in origin. Lymphoma-infiltrated tissues tend to have reduced levels of Mtap mRNA and MTAP protein in addition to unaltered levels of methyldeoxycytidine. These studies show that Mtap is a tumor suppressor gene independent of CDKN2A and

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Section: Discussionsupporting

confidence: 94%

Mice Heterozygous for Germ-line Mutations in Methylthioadenosine Phosphorylase (MTAP) Die Prematurely of T-Cell Lymphoma

Kadariya¹,

Yin

Tang³

et al. 2009

Cancer Research

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“…18 The 9p region includes the MTAP gene, which is disrupted by a de novo balanced translocation in a child with syndromic deafness. 19 We sequenced all exons and conserved intronic regions of TMC1 and MTAP in family DE, but did not identify novel variants segregating with deafness in either gene. The DFNA47 locus maps within the DFNB83 region at chr9:13 046 167-21 980 675.…”

Section: Novel Deafness Locimentioning

confidence: 99%

Five novel loci for inherited hearing loss mapped by SNP-based homozygosity profiles in Palestinian families

et al. 2009

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In communities with high rates of consanguinity and consequently high prevalence of recessive phenotypes, homozygosity mapping with SNP arrays is an effective approach for gene discovery. In 20 Palestinian kindreds with prelingual nonsyndromic hearing loss, we generated homozygosity profiles reflecting linkage to the phenotype. Family sizes ranged from small nuclear families with two affected children, one unaffected sibling, and parents to multigenerational kindreds with 12 affected relatives. By including unaffected parents and siblings and screening 250 K SNP arrays, even small nuclear families yielded informative profiles. In 14 families, we identified the allele responsible for hearing loss by screening a single candidate gene in the longest homozygous region. Novel alleles included missense, nonsense, and splice site mutations of CDH23, MYO7A, MYO15A, OTOF, PJVK, Pendrin/SLC26A4, TECTA, TMHS, and TMPRSS3, and a large genomic deletion of Otoancorin (OTOA). All point mutations were rare in the Palestinian population (zero carriers in 288 unrelated controls); the carrier frequency of the OTOA genomic deletion was 1%. In six families, we identified five genomic regions likely to harbor novel genes for human hearing loss on chromosomes 1p13.3 (DFNB82), 9p23-p21.2/p13.3-q21.13 (DFNB83), 12q14.3-q21.2 (DFNB84; two families), 14q23.1-q31.1, and 17p12-q11.2 (DFNB85).

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“…More than a decade ago, the Mendelian Cytogenetics Network (MCN) was established to study DBCRs in a systematic fashion (Tommerup 1993;Bugge et al 2000), and, more recently, similar programs to characterize DBCRs have been initiated elsewhere (Alkuraya et al 2006;Lu et al 2007;Williamson et al 2007).…”

Section: Genome Research 1145mentioning

confidence: 99%

Mapping translocation breakpoints by next-generation sequencing

Chen¹,

Kalscheuer²,

Tzschach³

et al. 2008

Genome Res.

122

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Balanced chromosome rearrangements (BCRs) can cause genetic diseases by disrupting or inactivating specific genes, and the characterization of breakpoints in disease-associated BCRs has been instrumental in the molecular elucidation of a wide variety of genetic disorders. However, mapping chromosome breakpoints using traditional methods, such as in situ hybridization with fluorescent dye-labeled bacterial artificial chromosome clones (BAC-FISH), is rather laborious and time-consuming. In addition, the resolution of BAC-FISH is often insufficient to unequivocally identify the disrupted gene. To overcome these limitations, we have performed shotgun sequencing of flow-sorted derivative chromosomes using “next-generation” (Illumina/Solexa) multiplex sequencing-by-synthesis technology. As shown here for three different disease-associated BCRs, the coverage attained by this platform is sufficient to bridge the breakpoints by PCR amplification, and this procedure allows the determination of their exact nucleotide positions within a few weeks. Its implementation will greatly facilitate large-scale breakpoint mapping and gene finding in patients with disease-associated balanced translocations.

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Methylthioadenosine phosphorylase (MTAP) in hearing: Gene disruption by chromosomal rearrangement in a hearing impaired individual and model organism analysis

Cited by 12 publications

References 36 publications

Mice Heterozygous for Germ-line Mutations in Methylthioadenosine Phosphorylase (MTAP) Die Prematurely of T-Cell Lymphoma

Mice Heterozygous for Germ-line Mutations in Methylthioadenosine Phosphorylase (MTAP) Die Prematurely of T-Cell Lymphoma

Five novel loci for inherited hearing loss mapped by SNP-based homozygosity profiles in Palestinian families

Mapping translocation breakpoints by next-generation sequencing

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