Transcription Factor SOX3 Is Involved in X-Linked Mental Retardation with Growth Hormone Deficiency

• Published in: American journal of human genetics Vol. 71; no. 6; pp. 1450 - 1455
• Main Authors: Laumonnier, Frédéric, Ronce, Nathalie, Hamel, Ben C.J., Thomas, Paul, Lespinasse, James, Raynaud, Martine, Paringaux, Christine, van Bokhoven, Hans, Kalscheuer, Vera, Fryns, Jean-Pierre, Chelly, Jamel, Moraine, Claude, Briault, Sylvain
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.12.2002; University of Chicago Press; Elsevier (Cell Press); The American Society of Human Genetics
• Subjects: Adult and adolescent clinical studies; Biological and medical sciences; Chromosome Breakage - genetics; Chromosome Inversion; Chromosomes, Human, X - genetics; DNA-Binding Proteins - genetics; Female; Gene Expression Regulation, Developmental; Genetic Linkage - genetics; Genetics; High Mobility Group Proteins - genetics; Human Growth Hormone - deficiency; Humans; Intellectual deficiency; Life Sciences; Male; Medical sciences; Mental Retardation, X-Linked - genetics; Molecular Sequence Data; Mutation - genetics; Pedigree; Peptides - genetics; Polymorphism, Genetic - genetics; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; SOXB1 Transcription Factors; Transcription Factors; Human; Sex linked character; Pathogenesis; Deficiency; Somatotropin hormone; Developmental disorder; Mental retardation; Genetic determinism; Genetic disease; Intellectual deficiency; Female; Psychopathology; X-Chromosome; Transcription factor
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/344661

Physical mapping of the breakpoints of a pericentric inversion of the X chromosome (46,X,inv[X][p21q27]) in a female patient with mild mental retardation revealed localization of the Xp breakpoint in the IL1RAPL gene at Xp21.3 and the Xq breakpoint near the SOX3 gene (SRY [ sex determining region Y]–box 3) (GenBank accession number NM_005634) at Xq26.3. Because carrier females with microdeletion in the IL1RAPL gene do not present any abnormal phenotype, we focused on the Xq breakpoint. However, we were unable to confirm the involvement of SOX3 in the mental retardation in this female patient. To validate SOX3 as an X-linked mental retardation (XLMR) gene, we performed mutation analyses in families with XLMR whose causative gene mapped to Xq26-q27. We show here that the SOX3 gene is involved in a large family in which affected individuals have mental retardation and growth hormone deficiency. The mutation results in an in-frame duplication of 33 bp encoding for 11 alanines in a polyalanine tract of the SOX3 gene. The expression pattern during neural and pituitary development suggests that dysfunction of the SOX3 protein caused by the polyalanine expansion might disturb transcription pathways and the regulation of genes involved in cellular processes and functions required for cognitive and pituitary development.