Association of an X-chromosome dodecamer insertional variant allele with mental retardation

R A Philibert; B H King; S Winfield; E H Cook; Y H Lee; B Stubblefield; P Damschroder-Williams; C Dea; A Palotie; C Tengstrom; B M Martin; E I Ginns

doi:10.1038/sj.mp.4000442

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Association of an X-chromosome dodecamer insertional variant allele with mental retardation

Journal article

Peer reviewed

Association of an X-chromosome dodecamer insertional variant allele with mental retardation

R A Philibert, B H King, S Winfield, E H Cook, Y H Lee, B Stubblefield, P Damschroder-Williams, C Dea, A Palotie, C Tengstrom, …

Molecular psychiatry, Vol.3(4), pp.303-309

07/1998

DOI: 10.1038/sj.mp.4000442

PMID: 9702738

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Abstract

Mental retardation is a prominent feature of many neurodevelopmental syndromes. In an attempt to identify genetic components of these illnesses, we isolated and sequenced a large number of human genomic cosmid inserts containing large trinucleotide repeats. One of these cosmids, Cos-4, maps to the X-chromosome and contains the sequence of a 7.3-kb mRNA. Initial polymorphism analysis across a region of repetitive DNA in this gene revealed a rare 12-bp exonic variation (<< 1% in non-iII males) having an increased prevalence in non-Fragile X males with mental retardation (4%, P < 0.04, n = 81). This variant was not present in the highly conserved mouse homologue that has 100% amino acid identity to the human sequence near the polymorphism. Subsequent screening of two additional independent cohorts of non-Fragile X mentally retarded patients and ethnically matched controls demonstrated an even higher prevalence of the 12-bp variant in males with mental retardation (8%, P < 0.0003, n = 125, and 14%, P < 0.10, n = 36) vs the controls. Multivariate analysis was conducted in an effort to identify other phenotypic components in affected individuals, and the findings suggested an increased incidence of histories of hypothyroidism (P < 0.001) and treatment with antidepressants (P < 0.001). We conclude that the presence of this 12-bp variant confers significant susceptibility for mental retardation.

Trinucleotide Repeats

Prevalence

Exons

Humans

Molecular Sequence Data

Male

Intellectual Disability - genetics

Genetic Variation

Base Sequence

Conserved Sequence

Female

Hypothyroidism - epidemiology

Hypothyroidism - genetics

Fragile X Syndrome - genetics

Amino Acid Sequence

Cosmids

Gene Library

California - epidemiology

Europe - epidemiology

In Situ Hybridization, Fluorescence

Chromosome Mapping

DNA Transposable Elements

Polymorphism, Genetic

Sequence Homology, Amino Acid

Sequence Alignment

Animals

Alleles

X Chromosome

Mice

Finland - epidemiology

Details

Title: Subtitle: Association of an X-chromosome dodecamer insertional variant allele with mental retardation
Creators: R A Philibert - Clinical Neuroscience Branch, National Institute of Mental Health, Bethesda, MD 20892, USA. philiber@irp.nimh.nih.gov
B H King
S Winfield
E H Cook
Y H Lee
B Stubblefield
P Damschroder-Williams
C Dea
A Palotie
C Tengstrom
B M Martin
E I Ginns
Resource Type: Journal article
Publication Details: Molecular psychiatry, Vol.3(4), pp.303-309
DOI: 10.1038/sj.mp.4000442
PMID: 9702738
NLM abbreviation: Mol Psychiatry
ISSN: 1359-4184
eISSN: 1476-5578
Publisher: England
Grant note: R01 MH52223 / NIMH NIH HHS R01 MH33779 / NIMH NIH HHS K02 MH01389 / NIMH NIH HHS
Language: English
Date published: 07/1998
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Psychiatry; Iowa Neuroscience Institute
Record Identifier: 9984003987602771

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