Mutation of ALMS1, a large gene with a tandem repeat encoding 47 amino acids, causes Alstrom syndrome
Mutation of ALMS1, a large gene with a tandem repeat encoding 47 amino acids, causes Alstrom syndrome
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DOI：
10.1038/ng874
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发表时间：
2002-05-01
期刊：
影响因子：
30.8
通讯作者：
Wilson, DI
中科院分区：
文献类型：
--
作者：
Hearn, T;Renforth, GL;Wilson, DI
Alstrom综合征（OMIM 203800）是一种常染色体隐性遗传疾病，其特征为锥-杆视网膜营养不良、心肌病和2型糖尿病，已定位于染色体2 p13（参考文献1-5）。我们研究了一个Alstrom综合征携带家族性平衡相互染色体易位（46，XY，t（2;11）（p13; q21）mat）涉及以前涉及的关键区域的个人。我们假设这个个体是一个复合杂合子，携带一个被易位破坏的基因拷贝，另一个被基因内突变破坏。我们将母体等位基因上的2 p13断裂点映射到1.7 kb的基因组片段，该片段包含新发现的基因（ALMS 1）的外显子4和外显子5的起始;我们在该基因的父系拷贝中检测到移码突变。ALMS 1的12.9 kb转录本编码4，169个氨基酸的蛋白质，其功能未知。该蛋白质含有一个大的串联重复结构域，包括47个氨基酸的34个不完全重复。我们在7个家族中检测到6种不同的突变（2种无义突变和4种导致过早终止密码子的移码突变），证实ALMS 1是Alstrom综合征的潜在基因。我们认为ALMS 1是第一个人类疾病基因的特点是常染色体隐性遗传被确定为一个平衡的相互易位的结果。
Alstrom syndrome (OMIM 203800) is an autosomal recessive disease, characterized by cone-rod retinal dystrophy, cardiomyopathy and type 2 diabetes mellitus, that has been mapped to chromosome 2p13 (refs 1-5). We have studied an individual with Alstrom syndrome carrying a familial balanced reciprocal chromosome translocation (46, XY, t(2;11)(p13; q21)mat) involving the previously implicated critical region. We postulated that this individual was a compound heterozygote, carrying one copy of a gene disrupted by the translocation and the other copy disrupted by an intragenic mutation. We mapped the 2p13 breakpoint on the maternal allele to a genomic fragment of 1.7 kb which contains exon 4 and the start of exon 5 of a newly discovered gene (ALMS1); we detected a frameshift mutation in the paternal copy of the gene. The 12.9-kb transcript of ALMS1 encodes a protein of 4,169 amino acids whose function is unknown. The protein contains a large tandem-repeat domain comprising 34 imperfect repetitions of 47 amino acids. We have detected six different mutations (two nonsense and four frameshift mutations causing premature stop codons) in seven families, confirming that ALMS1 is the gene underlying Alstrom syndrome. We believe that ALMS1 is the first human disease gene characterized by autosomal recessive inheritance to be identified as a result of a balanced reciprocal translocation.