Keratosis Follicularis Spinulosa Decalvans Is Caused by Mutations in MBTPS2
Keratosis Follicularis Spinulosa Decalvans Is Caused by Mutations in MBTPS2
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DOI：
10.1002/humu.21335
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发表时间：
2010-10-01
期刊：
影响因子：
3.9
通讯作者：
den Dunnen, Johan T.
中科院分区：
文献类型：
--
作者：
Aten, Emmelien;Brasz, Lisa C.;den Dunnen, Johan T.
毛囊角化病是一种罕见的遗传性疾病，其特征是在头皮上出现过度角化的毛囊丘疹，随后是头皮、睫毛和眉毛的进行性脱发。相关的眼部表现包括儿童期眼恐怖症和角膜营养不良。由于类似疾病的遗传和临床异质性，KFSD的明确诊断通常具有挑战性。为了鉴定致病基因，我们重新分析了一个大型荷兰KFSD家族。SNP阵列（1 M）将基因座重新定义为Xp22.12-Xp22.11处的2.9-Mb区域。对候选区域中的所有14个基因的筛选鉴定MBTPS 2为携带c.1523A>G（p.Asn508Ser）错义突变的候选基因。在两个不相关的X连锁KFSD家族中也发现了该变异体，并在所有家族中与KFSD共分离。在有症状的女性携带者中，正常等位基因的偏斜X失活与症状的严重程度增加相匹配。MBTPS 2是切割固醇调节元件结合蛋白（SREBP）所必需的。体外功能表达研究。1523 A>G突变显示甾醇反应性降低一半。最近在IFAP综合征患者中发现了MBTPS 2的其他错义突变。我们假设，这两种表型是在一个遗传疾病的频谱与部分重叠的表型。Mutat 31：1125-1133，2010. (C)2010 Wiley-Liss，Inc.
Keratosis Follicularis Spinulosa Decalvans (KFSD) is a rare genetic disorder characterized by development of hyperkeratotic follicular papules on the scalp followed by progressive alopecia of the scalp, eyelashes, and eyebrows. Associated eye findings include photophobia in childhood and corneal dystrophy. Due to the genetic and clinical heterogeneity of similar disorders, a definitive diagnosis of KFSD is often challenging. Toward identification of the causative gene we reanalyzed a large Dutch KFSD family. SNP arrays (1 M) redefined the locus to a 2.9-Mb region at Xp22.12-Xp22.11. Screening of all 14 genes in the candidate region identified MBTPS2 as the candidate gene carrying a c.1523A>G (p.Asn508Ser) missense mutation. The variant was also identified in two unrelated X-linked KFSD families and cosegregated with KFSD in all families. In symptomatic female carriers, skewed X-inactivation of the normal allele matched with increased severity of symptoms. MBTPS2 is required for cleavage of sterol regulatory element-binding proteins (SREBPs). In vitro functional expression studies of the c. 1523A>G mutation showed that sterol responsiveness was reduced by half. Other missense mutations in MBTPS2 have recently been identified in patients with IFAP syndrome. We postulate that both phenotypes are in the spectrum of one genetic disorder with a partially overlapping phenotype. Hum Mutat 31:1125-1133, 2010. (C) 2010 Wiley-Liss, Inc.