Hearn Tom, Renforth Glenn L, Spalluto Cosma, Hanley Neil A, Piper Karen, Brickwood Sarah, White Chris, Connolly Vincent, Taylor James F N, Russell-Eggitt Isabelle, Bonneau Dominque, Walker Mark, Wilson David I
Division of Human Genetics, Southampton University, The Duthie Building, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK.
Nat Genet. 2002 May;31(1):79-83. doi: 10.1038/ng874. Epub 2002 Apr 8.
Alström 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 Alström 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 Alström 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.
阿尔斯特伦综合征（OMIM 203800）是一种常染色体隐性疾病，其特征为锥杆型视网膜营养不良、心肌病和2型糖尿病，该疾病已被定位到2号染色体的p13区域（参考文献1 - 5）。我们研究了一名患有阿尔斯特伦综合征的个体，其携带一种家族性平衡相互染色体易位（46, XY,t(2;11)(p13;q21)mat），涉及先前认为的关键区域。我们推测该个体为复合杂合子，携带一个因易位而破坏的基因拷贝以及另一个因基因内突变而破坏的拷贝。我们将母本等位基因上的2p13断点定位到一个1.7 kb的基因组片段，该片段包含一个新发现基因（ALMS1）的第4外显子和第5外显子的起始部分；我们在该基因的父本拷贝中检测到一个移码突变。ALMS1的12.9 kb转录本编码一个由4169个氨基酸组成的蛋白质，其功能未知。该蛋白质包含一个大的串联重复结构域，由34个47个氨基酸的不完全重复序列组成。我们在7个家系中检测到6种不同的突变（2个无义突变和4个导致过早终止密码子的移码突变），证实ALMS1是阿尔斯特伦综合征的致病基因。我们认为ALMS1是第一个因常染色体隐性遗传而被鉴定的人类疾病基因，其鉴定结果是由于平衡相互易位导致的。
