Crackower M A, Scherer S W, Rommens J M, Hui C C, Poorkaj P, Soder S, Cobben J M, Hudgins L, Evans J P, Tsui L C
Department of Molecular and Medical Genetics, University of Toronto, Canada.
Hum Mol Genet. 1996 May;5(5):571-9. doi: 10.1093/hmg/5.5.571.
Split hand/split foot malformation (SHFM) is a heterogeneous limb developmental disorder, characterized by missing digits and fusion of remaining digits. An autosomal dominant form of this disorder (SHFM1) has been mapped to 7q21.3-q22.1 on the basis of SHFM-associated chromosomal rearrangements. Utilizing a YAC contig across this region, we have defined a critical interval of 1.5 Mb by the analysis of six interstitial deletion patients and mapped the translocation breakpoints of seven ectrodactyly patients within the interval. To delineate the basic molecular defect underlying SHFM, we have searched for candidate genes in a 500 kb region containing five of the translocation breakpoints. Three genes were identified, two genes of the Distal-less (dii) homeobox gene family, DLX5 and DLX6 and a novel gene, which we named DSS1. DSS1 is predicted to encode a highly acidic polypeptide with no significant similarity to any known proteins but 100% amino acid sequence identify with its murine homolog (Dss1). Using RNA in situ hybridization analysis, we detected a tissue-specific expression profile for Dss1 in limb bud, craniofacial primordia and skin. A deficiency in expression of Dss1, DLX5 and/or DLX6 during development may explain the SHFM phenotypes.
裂手/裂足畸形（SHFM）是一种异质性肢体发育障碍，其特征为指（趾）缺如以及剩余指（趾）融合。基于与SHFM相关的染色体重排，该疾病的常染色体显性形式（SHFM1）已被定位到7q21.3 - q22.1。利用跨越该区域的酵母人工染色体（YAC）重叠群，我们通过分析6例间质性缺失患者确定了一个1.5 Mb的关键区间，并将7例裂指（趾）患者的易位断点定位在该区间内。为了阐明SHFM潜在的基本分子缺陷，我们在一个包含5个易位断点的500 kb区域内寻找候选基因。鉴定出了3个基因，即远端缺失（Distal-less，dll）同源框基因家族的2个基因DLX5和DLX6，以及一个新基因，我们将其命名为DSS1。预测DSS1编码一种高度酸性的多肽，与任何已知蛋白质均无明显相似性，但其氨基酸序列与小鼠同源物（Dss1）100%相同。通过RNA原位杂交分析，我们检测到Dss1在肢芽、颅面原基和皮肤中有组织特异性表达谱。发育过程中Dss1、DLX5和/或DLX6表达的缺陷可能解释了SHFM的表型。
