Mutations in the guanine nucleotide exchange factor gene IQSEC2 cause nonsyndromic intellectual disability

The first family identified as having a nonsyndromic intellectual disability was mapped in 1988. Here we show that a mutation of IQSEC2, encoding a guanine nucleotide exchange factor for the ADP-ribosylation factor family of small GTPases, caused this disorder. In addition to MRX1, IQSEC2 mutations...

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Published inNature genetics Vol. 42; no. 6; pp. 486 - 488
Main Authors Proos, Anne, Gécz, Jozef, Hackett, Anna, Ramsden, Sarah L, Shoubridge, Cheryl, Gardner, Alison, Stratton, Michael R, Harvey, Robert J, Raymond, F Lucy, Field, Michael, Murphy, Jessica A, Puusepp, Helen, Schwartz, Charles E, Shaw, Marie, Turner, Gill, Abidi, Fatima, Walikonis, Randall S, Futreal, P Andrew, Tarpey, Patrick S, Stevenson, Roger E, Rujirabanjerd, Sinitdhorn, Boyle, Jackie
Format Journal Article
LanguageEnglish
Published New York, NY Nature Publishing Group 01.06.2010
Subjects
Adenosine diphosphate
Adult and adolescent clinical studies
Biological and medical sciences
Chromosomes
Chromosomes, Human, X
Comparative analysis
Diagnosis
Disability
Female
Fundamental and applied biological sciences. Psychology
Gene mutations
Genes
Genetic aspects
Genetics of eukaryotes. Biological and molecular evolution
Guanine Nucleotide Exchange Factors - genetics
Health aspects
Humans
Intellectual deficiency
Male
Medical sciences
Mental illness
Mental Retardation, X-Linked - genetics
Mutation
Pedigree
Proteins
Psychology. Psychoanalysis. Psychiatry
Psychopathology. Psychiatry
Risk factors
Studies
United States
United Kingdom
Handicap
Intellectual deficiency
Developmental disorder
Mutation
Gene
Mental retardation
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Summary:The first family identified as having a nonsyndromic intellectual disability was mapped in 1988. Here we show that a mutation of IQSEC2, encoding a guanine nucleotide exchange factor for the ADP-ribosylation factor family of small GTPases, caused this disorder. In addition to MRX1, IQSEC2 mutations were identified in three other families with X-linked intellectual disability. This discovery was made possible by systematic and unbiased X chromosome exome resequencing.
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AUTHOR CONTRIBUTIONS
C.S., M.S., F.A., A.G. and J.B. assembled the extended families and confirmed, tracked and analyzed the changes. A.P., H.P. and M.S. performed additional subject and control screening. P.S.T., A.F. and M.R.S. supervised the X-chromosome sequencing, collation and analysis of the sequencing data. A.H., M.F., R.E.S., G.T., C.E.S. and F.L.R. contributed families and clinical data on affected individuals. C.S., S.L.R., J.A.M., R.S.W., R.J.H. and S.R. performed functional assays. C.S. and J.G. conceived and designed the study and wrote the first draft of the manuscript. J.G. directed the study. All authors contributed to discussion of the results and manuscript preparation.
ISSN:1061-4036
1546-1718
DOI:10.1038/ng.588