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 Zmax = 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.
Laboratory of Clinical Neurogenetics, Wadsworth Center, New York State Department of Health, Albany 12201-0509, USA. jhiggins@wadsworth.org
J J
JJ
Higgins
D R
DR
Rosen
J M
JM
Loveless
J C
JC
Clyman
M J
MJ
Grau
D000328:Adult; D015220:Calcium Channels / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000235:genetics; D002648:Child; D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3; D004276:DNA, Satellite / Q000032:analysis; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008607:Intellectual Disability / Q000235:genetics*; D039841:Leukocyte L1 Antigen Complex; D051847:Lithostathine; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics
C497612:AD7c-NTP protein, human; D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D004276:DNA, Satellite; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D039841:Leukocyte L1 Antigen Complex; D051847:Lithostathine; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; D018160:Receptors, Cytoplasmic and Nuclear