Ansar Muhammad, Jan Abid, Santos-Cortez Regie Lyn P, Wang Xin, Suliman Muhammad, Acharya Anushree, Habib Rabia, Abbe Izoduwa, Ali Ghazanfar, Lee Kwanghyuk, Smith Joshua D, Nickerson Deborah A, Shendure Jay, Bamshad Michael J, Ahmad Wasim, Leal Suzanne M
Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Eur J Hum Genet. 2016 Aug;24(8):1223-7. doi: 10.1038/ejhg.2015.260. Epub 2015 Dec 23.
Alopecia with mental retardation (APMR) is a very rare disorder. In this study, we report on a consanguineous Pakistani family (AP91) with mild-to-moderate intellectual disability, adolescent alopecia and dentogingival abnormalities. Using homozygosity mapping, linkage analysis and exome sequencing, we identified a novel rare missense variant c.898G>A (p.(Glu300Lys)) in ITGB6, which co-segregates with the phenotype within the family and is predicted to be deleterious. Structural modeling shows that Glu300 lies in the β-propeller domain, and is surrounded by several residues that are important for heterodimerization with α integrin. Previous studies showed that ITGB6 variants can cause amelogenesis imperfecta in humans, but patients from family AP91 who are homozygous for the c.898G>A variant present with neurological and dermatological features, indicating a role for ITGB6 beyond enamel formation. Our study demonstrates that a rare deleterious variant within ITGB6 causes not only dentogingival anomalies but also intellectual disability and alopecia.
伴有智力障碍的脱发症（APMR）是一种非常罕见的疾病。在本研究中，我们报告了一个近亲结婚的巴基斯坦家庭（AP91），该家庭成员存在轻度至中度智力残疾、青少年脱发以及牙龈异常。通过纯合性定位、连锁分析和外显子组测序，我们在整合素β6（ITGB6）中鉴定出一个新的罕见错义变异c.898G>A（p.(Glu300Lys)），该变异与家族中的表型共分离，并且预测具有有害性。结构建模显示，Glu300位于β-螺旋桨结构域，周围环绕着几个对于与α整合素异二聚化很重要的残基。先前的研究表明，ITGB6变异可导致人类牙釉质发育不全，但AP91家族中c.898G>A变异纯合的患者表现出神经学和皮肤病学特征，这表明ITGB6在牙釉质形成之外还具有其他作用。我们的研究表明，ITGB6内的一种罕见有害变异不仅会导致牙龈异常，还会导致智力残疾和脱发。
