A gene for nonsyndromic mental retardation maps to chromosome 3p25-pter

Objective: To establish genetic linkage between polymorphic microsatellite loci and a disease locus responsible for an autosomal recessive type of nonsyndromic mental retardation (MR). Background: Although MR is the most common developmental disability in the United States, the etiologies of most nonsyndromic cases are not known. Methods: A genealogic database provided information to reconstruct the relationships between 32 individuals from five nuclear families in a single pedigree with 10 affected individuals with nonsyndromic MR. To find a MR disease locus in this population, we performed a genome-wide search using genetic loci spaced at 10- to 20-cM intervals. Pairwise linkage analysis, multipoint linkage analysis, and haplotype reconstruction were used to localize the disease gene. Results: Genetic linkage between a MR disease locus and locus D3S3050 on chromosome 3p25-pter was established with a Z(max) = 9.18 at theta = 0.00. Fine mapping this region delimited a 13.47-cM candidate interval defined by key recombinants at loci D3S3525 and D3S1304. Multipoint linkage analysis refined the critical region to a 6.71-cM interval flanked by loci D3S3525 and D3S1560. Evidence that a gene for MR resides in this location is supported by previous breakpoint deletion mapping studies performed in the chromosome 3p- syndrome. Conclusions: These results suggest that a gene on the subtelomeric region of chromosome 3p contributes to general intelligence. The genes for the cell adhesion L1-like molecule (CALL), the inositol triphosphate receptor (ITPR1), and the AD neuronal thread protein (AD7c-NTP) are leading positional candidates because of their role in brain development, neuronal signaling, and structure.