Cappuccio Gerarda, Pinelli Michele, Torella Annalaura, Alagia Marianna, Auricchio Renata, Staiano Annamaria, Nigro Vincenzo, Brunetti-Pierri Nicola
Department of Translational Medicine, Section of Pediatrics, Federico II University, Naples, Italy.
Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy.
Am J Med Genet A. 2017 Oct;173(10):2743-2746. doi: 10.1002/ajmg.a.38367. Epub 2017 Aug 2.
The gene DST encodes for the large protein BPAG1 involved in hemidesmosomes. Its alternative splicing gives rise to tissue-enriched isoforms in brain, muscle, and skin. The few patients described so far with bi-allelic mutations in the DST gene have either a skin phenotype of epidermolysis bullosa simplex or a neurological phenotype. Here, we report a 17-year-old female individual presenting with a more complex phenotype consisting of both skin and neuronal involvement, in addition to several previously unreported findings, such as iris heterochromia, cataract, hearing impairment, syringomyelia, behavioral, and gastrointestinal issues, osteoporosis, and growth hormone deficiency. Family-trio whole exome sequencing revealed that she was a compound heterozygous for two variants in the DST gene with highly-predicted functional impact, c.3886A>G (p.R1296X) in exon 29 and c.806C>T (p.H269R) in exon 7. Interestingly, exon 7 is included in the neuronal isoform whereas exon 29 is expressed in both skin and neuronal isoforms. The patient we described is the first case with a mutation affecting an exon expressed in both the neuronal and skin isoforms that can explain the more complex phenotype compared to previously reported cases.
基因DST编码参与半桥粒的大蛋白BPAG1。其可变剪接产生在脑、肌肉和皮肤中组织富集的异构体。迄今为止描述的少数DST基因双等位基因突变患者，要么具有单纯性大疱性表皮松解症的皮肤表型，要么具有神经学表型。在此，我们报告一名17岁女性个体，除了一些先前未报告的发现，如虹膜异色症、白内障、听力障碍、脊髓空洞症、行为和胃肠道问题、骨质疏松症以及生长激素缺乏外，还表现出由皮肤和神经元受累组成的更复杂表型。家系三联体全外显子组测序显示，她是DST基因中两个具有高度预测功能影响的变体的复合杂合子，分别是外显子29中的c.3886A>G（p.R1296X）和外显子7中的c.806C>T（p.H269R）。有趣的是，外显子7包含在神经元异构体中，而外显子29在皮肤和神经元异构体中均有表达。我们描述的患者是首例具有影响在神经元和皮肤异构体中均表达的外显子的突变的病例，这可以解释与先前报道病例相比更复杂的表型。
