Higgins J J, Rosen D R, Loveless J M, Clyman J C, Grau M J
Laboratory of Clinical Neurogenetics, Wadsworth Center, New York State Department of Health, Albany 12201-0509, USA.
Neurology. 2000 Aug 8;55(3):335-40. doi: 10.1212/wnl.55.3.335.
To establish genetic linkage between polymorphic microsatellite loci and a disease locus responsible for an autosomal recessive type of nonsyndromic mental retardation (MR).
Although MR is the most common developmental disability in the United States, the etiologies of most nonsyndromic cases are not known.
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.
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.
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.
在多态性微卫星位点与导致常染色体隐性非综合征型智力迟钝（MR）的疾病位点之间建立遗传连锁关系。
尽管智力迟钝是美国最常见的发育障碍，但大多数非综合征型病例的病因尚不清楚。
一个系谱数据库提供了信息，用于重建来自一个单一家系中五个核心家庭的32个人之间的关系，其中有10个患有非综合征型MR的个体。为了在该人群中找到一个MR疾病位点，我们使用间隔为10至20厘摩（cM）的遗传位点进行了全基因组搜索。采用成对连锁分析、多点连锁分析和单倍型重建来定位疾病基因。
在染色体3p25 - pter上的MR疾病位点与D3S3050位点之间建立了遗传连锁关系，在θ = 0.00时Zmax = 9.18。对该区域进行精细定位，确定了一个由位点D3S3525和D3S1304处的关键重组体定义的13.47厘摩候选区间。多点连锁分析将关键区域细化为一个由位点D3S3525和D3S1560侧翼的6.71厘摩区间。之前在3p - 综合征染色体上进行的断点缺失定位研究支持了MR基因位于该位置的证据。
这些结果表明，位于染色体3p亚端粒区域的一个基因对一般智力有影响。细胞粘附L1样分子（CALL）、肌醇三磷酸受体（ITPR1）和AD神经元丝蛋白（AD7c - NTP）的基因因其在脑发育、神经元信号传导和结构中的作用而成为主要的位置候选基因。
