研究人员揭示了导致患者没有指纹的一种罕见疾病背后的突变
2007年，一位20多岁的瑞士妇女在进入美国边境时遇到了难以想象的麻烦。海关官员无法确认她的身份。这位妇女护照上的照片与她的脸能够完全吻合，但是当工作人员对她的手进行扫描时却发现了一个令人震惊的结果：她没有指纹。
事实证明，这位妇女患有一种极为罕见的疾病——皮纹病（adermatoglyphia）。瑞士巴塞尔大学医院的皮肤科医生Peter Itin将这种疾病戏称为“移民延期病”，因为患者想要进入外国将是非常困难的。与普通人相比，除了光滑的指尖外，他们分泌的手汗也较少。然而科学家对于究竟是什么原因导致了这种疾病却知之甚少。
由于在这个大家庭中有9位女性成员都没有指纹，Itin和他的同事——包括以色列特拉维夫Sourasky医学中心的皮肤科医生Eli Sprecher——怀疑可能是遗传学因素导致了这种疾病。因此他们从这个家族中采集了脱氧核糖核酸（DNA）——在4名家族成员中仅有1人被证明患有皮纹病，并将患病家族成员的基因组与具有正常指纹的家庭成员的基因组进行了对比。研究人员随后在接近这些基因的17个区域发现了差异。随后他们对这些基因进行了测序，希望能够鉴别出罪魁祸首。
然而研究人员最终却一无所获。起初，Sprecher怀疑或者是他们的遗传分析工作出现了错误，或者有一些遗漏的突变隐藏在基因组中没有编码的或“垃圾”区域。他说：“随后机会来了。”当研究生Janna Nousbeck通过在线数据库对来自可疑区域的罕见DNA转录进行筛查时，她注意到一个非常短的序列重叠在名为SMARCAD1的一部分基因上。这个基因似乎很可能是造成突变的原因，因为它仅仅表达在皮肤中。
当研究人员对SMARCAD1进行测序后，他们的怀疑得到了证实——这一基因在指纹缺失的家族成员中发生了突变，但在其他家庭成员中却是正常的。这一突变并没有出现在编码SMARCAD1蛋白质的基因区域中，而是位于能够阻止SMARCAD1正确合成的一个关键剪接位点附近。研究人员在8月4日出版的《美国人类遗传学期刊》上报告了这一研究成果。
Sprecher的下一步工作是搞清SMARCAD1的确切功能，及其如何对指纹模式的形成造成影响——而这是另一个未解之谜。但是研究人员认为，这种基因可能在胎儿发育的早期阶段帮助皮肤细胞之间彼此交叠。
同样从事皮纹病研究的美国印第安纳波利斯市印第安纳大学医学院的分子遗传学家Terry Reed表示，他不能肯定是否每一位缺失指纹的患者都与SMARCAD1有关。他表示计划对自己的一名皮纹病患者进行基因测序分析。但是他说，“至少很高兴看到确定了一个与这种疾病相关的基因”，并且希望它可以帮助研究人员在大体上了解皮肤形成的过程。
生物探索推荐英文论文摘要：
A Mutation in a Skin-Specific Isoform of SMARCAD1 Causes Autosomal-Dominant Adermatoglyphia
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.
生物探索推荐英文原文报道：
The Mystery of the Missing Fingerprints
In 2007, a Swiss woman in her late 20s had an unusually hard time crossing the U.S. border. Customs agents could not confirm her identity. The woman's passport picture matched her face just fine, but when the agents scanned her hands, they discovered something shocking: she had no fingerprints.
The woman, it turns out, had an extremely rare condition known as adermatoglyphia. Peter Itin, a dermatologist at the University Hospital Basel in Switzerland, has dubbed it the "immigration delay disease" because sufferers have such a hard time entering foreign countries. In addition to smooth fingertips, they also produce less hand sweat than the average person. Yet scientists know very little about what causes the condition.
Since nine members of the woman's extended family also lacked fingerprints, Itin and his colleagues, including Eli Sprecher, a dermatologist at the Tel Aviv Sourasky Medical Center in Israel, suspected that the cause might be genetic. So they collected DNA from the family—one of only four ever documented with ADG—and compared the genomes of family members with ADG with those of members who had normal fingerprints. The researchers found differences in 17 regions that were close to genes. Then they sequenced these genes, expecting to identify the culprit.
But the researchers didn't find anything. At first, Sprecher suspected that either they had performed the genetic analysis incorrectly or the missing mutation was hiding in a noncoding or "junk" region of the genome. "Then came the trick," he says. When graduate student Janna Nousbeck sifted through online databases of rare DNA transcripts that came from the suspect regions, she noticed one very short sequence that overlapped with part of a gene called SMARCAD1. This gene seemed like a likely candidate for the mutation since it was only expressed in the skin.
When the researchers sequenced SMARCAD1, their suspicions were confirmed: The gene was mutated in the fingerprintless family members, but not in the other family members. The mutation isn't in a region of the gene that codes for the SMARCAD1 protein; instead it's near a key splicing site that prevents SMARCAD1 from being made correctly, the researchers report today in The American Journal of Human Genetics.
Sprecher's next mission is to find out what exactly the function of SMARCAD1 is and how it contributes to the formation of fingerprint patterns, another unsolved mystery. But the researchers think that the gene might help skin cells fold over one another early in fetal development.
Terry Reed, a molecular geneticist at Indiana University School of Medicine in Indianapolis, who has also studied ADG, says that he is unsure whether SMARCAD1 is responsible for every patient who lacks fingerprints. He says he plans to sequence the gene from one of his own ADG patients. But he says that it's "gratifying to at least see a gene identified for this condition" and hopes it may help researchers understand skin development in general.
