Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Am J Hum Genet. 2011 Aug 12;89(2):302-7. doi: 10.1016/j.ajhg.2011.07.004. Epub 2011 Aug 4.
Monogenic disorders offer unique opportunities for researchers to shed light upon fundamental physiological processes in humans. We investigated a large family affected with autosomal-dominant adermatoglyphia (absence of fingerprints) also known as the "immigration delay disease." Using linkage and haplotype analyses, we mapped the disease phenotype to 4q22. One of the genes located in this interval is SMARCAD1, a member of the SNF subfamily of the helicase protein superfamily. We demonstrated the existence of a short isoform of SMARCAD1 exclusively expressed in the skin. Sequencing of all SMARCAD1 coding and noncoding exons revealed a heterozygous transversion predicted to disrupt a conserved donor splice site adjacent to the 3' end of a noncoding exon uniquely present in the skin-specific short isoform of the gene. This mutation segregated with the disease phenotype throughout the entire family. Using a minigene system, we found that this mutation causes aberrant splicing, resulting in decreased stability of the short RNA isoform as predicted by computational analysis and shown by RT-PCR. Taken together, the present findings implicate a skin-specific isoform of SMARCAD1 in the regulation of dermatoglyph development.
单基因疾病为研究人员提供了独特的机会，以阐明人类基本的生理过程。我们研究了一个受常染色体显性遗传的无指纹（adermatoglyphia）疾病影响的大家族，该疾病也被称为“移民延迟疾病”。通过连锁和单倍型分析，我们将疾病表型映射到 4q22。该区间内的一个基因是 SMARCAD1，它是螺旋酶蛋白超家族的 SNF 亚家族的成员。我们证明了仅在皮肤中表达的 SMARCAD1 短亚型的存在。对所有 SMARCAD1 编码和非编码外显子进行测序，发现了一个杂合性转换，预测该转换会破坏紧邻非编码外显子 3'端的保守供体位点，该非编码外显子仅存在于基因的皮肤特异性短亚型中。该突变在整个家族中与疾病表型共分离。使用小基因系统，我们发现该突变导致异常剪接，导致短 RNA 亚型的稳定性降低，这正如计算分析所预测的，并通过 RT-PCR 所示。综上所述，这些发现表明 SMARCAD1 的皮肤特异性亚型参与了皮肤纹理发育的调控。
