PDF(Pubmed)
Abstract：
Split Hand-Foot Malformation (SHFM) is a congenital limb defect characterized by a median cleft of the hands and/or feet due to the absence/hypoplasia of the central rays. It may occur as part of a syndromic condition or as an isolated malformation. The most common of the six genetic loci identified for this condition is correlated to SHFM1 and maps in the 7q21q22 region. SHFM1 is characterized by autosomal dominant transmission, incomplete penetrance and variable expressivity. Associated features often include hearing loss, intellectual disability/developmental delay and craniofacial abnormalities. Disruption of the DLX5/DLX6 genes, mapping within the SHFM1 locus, is now known to be responsible for the phenotype. Through SNP array, we analyzed a patient affected by SHFM1 associated with deafness and an abnormality of the inner ear (incomplete partition type I); we identified a deletion in 7q21, not involving the DLX5/6 genes, but including exons 15 and 17 of DYNC1I1, known to act as exonic enhancers (eExons) of the DLX5/6 genes. We further demonstrated the role of DYNC1I1 eExons in regulating DLX5/6 expression by means of showing a reduced expression of the DLX5/6 genes through RT-PCR in a patient-derived lymphoblastoid cell line. Furthermore, our data and a review of published cases do not support the hypothesis that DLX5/6 are imprinted in humans. This work is an example of how the disruption of regulatory elements can be responsible for congenital malformations.
摘要：
手脚分裂畸形（SHFM）是一种先天性肢体缺陷，其特征是由于中央射线的缺失/发育不全而导致手和/或脚的正中裂。它可能是综合征的一部分，也可能是孤立的畸形。在这种情况下确定的六个遗传基因座中，最常见的是与SHFM1和7q21q22区域的图谱相关。SHFM1以常染色体显性传递为特征，不完整的外显率和可变的表现力。相关特征通常包括听力损失，智力障碍/发育迟缓和颅面畸形。DLX5/DLX6基因的破坏，在SHFM1基因座内作图，现在已知是表型的原因。通过SNP阵列，我们分析了与耳聋和内耳异常相关的SHFM1患者（I型不完全分区）;我们在7q21中发现了一个缺失，不涉及DLX5/6基因，但包括DYNC1I1的外显子15和17，已知充当DLX5/6基因的外显子增强子（eExons）。我们通过在患者来源的淋巴母细胞细胞系中通过RT-PCR显示DLX5/6基因的表达降低，进一步证明了DYNC1I1e外显子在调节DLX5/6表达中的作用。此外，我们的数据和对已发表病例的回顾不支持DLX5/6在人类身上有印记的假设.这项工作是调节元件的破坏如何导致先天性畸形的一个例子。
