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

Robin E Williamson; Keith N Darrow; Sebastien Michaud; Julie S Jacobs; Marilyn C Jones; Daniel F Eberl; Richard L Maas; M Charles Liberman; Cynthia C Morton

doi:10.1002/ajmg.a.31724

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

Journal article

Peer reviewed

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

Robin E Williamson, Keith N Darrow, Sebastien Michaud, Julie S Jacobs, Marilyn C Jones, Daniel F Eberl, Richard L Maas, M Charles Liberman and Cynthia C Morton

American journal of medical genetics. Part A, Vol.143A(14), pp.1630-1639

07/15/2007

DOI: 10.1002/ajmg.a.31724

PMID: 17534888

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Abstract

Genes with a role in the auditory system have been mapped by genetic linkage analysis of families with heritable deafness and then cloned through positional candidate gene approaches. Another positional method for gene discovery is to ascertain deaf individuals with balanced chromosomal translocations and identify disrupted or disregulated genes at the site(s) of rearrangement. We report herein the use of fluorescence in situ hybridization (FISH) to map the breakpoint regions on each derivative chromosome of a de novo apparently balanced translocation, t(8;9)(q12.1;p21.3)dn, in a deaf individual. Chromosomal breakpoints were assigned initially by GTG-banding of metaphase chromosomes and then BAC probes chosen to map precisely the breakpoints by FISH experiments. To facilitate cloning of the breakpoint sequences, further refinement of the breakpoints was performed by FISH experiments using PCR products and by Southern blot analysis. The chromosome 9 breakpoint disrupts methylthioadenosine phosphorylase (MTAP); no known or predicted genes are present at the chromosome 8 breakpoint. Disruption of MTAP is hypothesized to lead to deafness due to the role of MTAP in metabolizing an inhibitor of polyamine synthesis. Drosophila deficient for the MTAP ortholog, CG4,802, were created and their hearing assessed; no hearing loss phenotype was observed. A knockout mouse model for MTAP deficiency was also created and no significant hearing loss was detected in heterozygotes for Mtap. Homozygous Mtap-deficient mice were embryonic lethal.

Immunohistochemistry

Translocation, Genetic

Humans

Embryo, Nonmammalian - metabolism

Child, Preschool

Molecular Sequence Data

Male

Purine-Nucleoside Phosphorylase - genetics

Genes, Lethal

Chromosomes, Human, Pair 9 - genetics

In Situ Hybridization

Base Sequence

Female

Purine-Nucleoside Phosphorylase - metabolism

Disease Models, Animal

Mice, Inbred C57BL

In Situ Hybridization, Fluorescence

Hearing Loss - pathology

Mice, Inbred Strains

Reverse Transcriptase Polymerase Chain Reaction

Mice, Knockout

Gene Expression Regulation, Enzymologic

Hearing Loss - genetics

Animals

Embryo, Nonmammalian - enzymology

Mice

Mutation

Drosophila melanogaster

Hearing Loss - enzymology

Details

Title: Subtitle: Methylthioadenosine phosphorylase (MTAP) in hearing: gene disruption by chromosomal rearrangement in a hearing impaired individual and model organism analysis
Creators: Robin E Williamson - Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA
Keith N Darrow
Sebastien Michaud
Julie S Jacobs
Marilyn C Jones
Daniel F Eberl
Richard L Maas
M Charles Liberman
Cynthia C Morton
Resource Type: Journal article
Publication Details: American journal of medical genetics. Part A, Vol.143A(14), pp.1630-1639
Publisher: United States
DOI: 10.1002/ajmg.a.31724
PMID: 17534888
ISSN: 1552-4825
eISSN: 1552-4833
Grant note: P30 DC5209 / NIDCD NIH HHS P01 GM061354 / NIGMS NIH HHS P30 DC005209 / NIDCD NIH HHS R01 DC0188 / NIDCD NIH HHS R01 DC004848-05 / NIDCD NIH HHS R01 DC000188 / NIDCD NIH HHS R01 DC000188-26 / NIDCD NIH HHS F31 DC005712 / NIDCD NIH HHS R01 DC004848-07 / NIDCD NIH HHS R01 DC000188-27 / NIDCD NIH HHS R01 DC04848 / NIDCD NIH HHS R01 DC004848 / NIDCD NIH HHS R01 DC004848-06 / NIDCD NIH HHS R01 DC03402 / NIDCD NIH HHS
Language: English
Date published: 07/15/2007
Academic Unit: Iowa Neuroscience Institute; Biology; Internal Medicine
Record Identifier: 9984070733602771

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