Ramot Yuval, Molho-Pessach Vered, Meir Tomer, Alper-Pinus Ruslana, Siam Ihab, Tams Spiro, Babay Sofia, Zlotogorski Abraham
Department of Dermatology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel The Center for Genetic Diseases of The Skin and Hair, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Department of Nephrology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
J Med Genet. 2014 Jun;51(6):388-94. doi: 10.1136/jmedgenet-2014-102346. Epub 2014 Mar 26.
The combination of palmoplantar keratoderma and woolly hair is uncommon and reported as part of Naxos and Carvajal syndromes, both caused by mutations in desmosomal proteins and associated with cardiomyopathy. We describe two large consanguineous families with autosomal-recessive palmoplantar keratoderma and woolly hair, without cardiomyopathy and with no mutations in any known culprit gene. The aim of this study was to find the mutated gene in these families.
Using whole-exome sequencing, we identified a homozygous missense c.2009C>T mutation in KANK2 in the patients (p.Ala670Val). KANK2 encodes the steroid receptor coactivator (SRC)-interacting protein (SIP), an ankyrin repeat containing protein, which sequesters SRCs in the cytoplasm and controls transcription activation of steroid receptors, among others, also of the vitamin D receptor (VDR). The mutation in KANK2 is predicted to abolish the sequestering abilities of SIP. Indeed, vitamin D-induced transactivation was increased in patient's keratinocytes. Furthermore, SRC-2 and SRC-3, coactivators of VDR and important components of epidermal differentiation, are localised to the nucleus of epidermal basal cells in patients, in contrast to the cytoplasmic distribution in the heterozygous control.
These findings provide evidence that keratoderma and woolly hair can be caused by a non-desmosomal mechanism and further underline the importance of VDR for normal hair and skin phenotypes.
掌跖角化病和羊毛状毛发同时出现的情况并不常见，被报道为纳克索斯综合征和卡瓦哈尔综合征的一部分，这两种综合征均由桥粒蛋白突变引起，并与心肌病相关。我们描述了两个近亲大家族，他们患有常染色体隐性遗传的掌跖角化病和羊毛状毛发，无心肌病，且任何已知的致病基因均无突变。本研究的目的是找出这些家族中的突变基因。
通过全外显子组测序，我们在患者中鉴定出KANK2基因存在纯合错义c.2009C>T突变（p.Ala670Val）。KANK2编码类固醇受体辅激活因子（SRC）相互作用蛋白（SIP），一种含有锚蛋白重复序列的蛋白，它将SRCs隔离在细胞质中，并控制类固醇受体的转录激活，其中也包括维生素D受体（VDR）的转录激活。预计KANK2中的突变会消除SIP的隔离能力。事实上，患者角质形成细胞中维生素D诱导的反式激活作用增强。此外，VDR的辅激活因子及表皮分化的重要成分SRC-2和SRC-3，在患者表皮基底细胞的细胞核中定位，这与杂合对照中的细胞质分布情况相反。
这些发现证明掌跖角化病和羊毛状毛发可能由非桥粒机制引起，并进一步强调了VDR对正常毛发和皮肤表型的重要性。
