Mutations in KCTD1 Cause Scalp-Ear-Nipple Syndrome
Mutations in KCTD1 Cause Scalp-Ear-Nipple Syndrome
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DOI：
10.1016/j.ajhg.2013.03.002
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发表时间：
2013-04-04
影响因子：
9.8
通讯作者：
Bamshad, Michael J.
中科院分区：
文献类型：
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作者：
Marneros, Alexander G.;Beck, Anita E.;Bamshad, Michael J.
头皮-耳-乳头（SEN）综合征是一种罕见的常染色体显性疾病，以头皮皮肤发育不全为特征；外耳、手指、指甲轻微畸形；以及乳房畸形。我们使用连锁分析和受SEN综合征影响的多重家族的外显子组测序来鉴定导致SEN综合征的钾通道四聚化结构域1 （KCTD1）突变。对受SEN综合征影响的10个家庭的评估显示，每个测试家庭都存在KCTD1错义突变。所有突变都发生在KCTD1区域，该区域编码高度保守的brick -a-brac， tram track和broad complex （BTB）结构域，这是转录抑制因子活性所必需的。KCTD1通过其BTB结构域抑制转录因子AP-2 α (TFAP2A)的反激活，而TFAP2A的突变导致患有branchiooculofacial syndrome （BOFS）的个体皮肤发育不全，这表明SEN综合征和BOFS的发病机制可能存在重叠。SEN综合征中KCTD1突变的鉴定揭示了这种含有btb结构域的转录抑制因子在外胚层发育过程中的作用。
Scalp-ear-nipple (SEN) syndrome is a rare, autosomal-dominant disorder characterized by cutis aplasia of the scalp; minor anomalies of the external ears, digits, and nails; and malformations of the breast. We used linkage analysis and exome sequencing of a multiplex family affected by SEN syndrome to identify potassium-channel tetramerization-domain-containing 1 (KCTD1) mutations that cause SEN syndrome. Evaluation of a total of ten families affected by SEN syndrome revealed KCTD1 missense mutations in each family tested. All of the mutations occurred in a KCTD1 region encoding a highly conserved bric-a-brac, tram track, and broad complex (BTB) domain that is required for transcriptional repressor activity. KCTD1 inhibits the transactivation of the transcription factor AP-2 alpha (TFAP2A) via its BTB domain, and mutations in TFAP2A cause cutis aplasia in individuals with branchiooculofacial syndrome (BOFS), suggesting a potential overlap in the pathogenesis of SEN syndrome and BOFS. The identification of KCTD1 mutations in SEN syndrome reveals a role for this BTB-domain-containing transcriptional repressor during ectodermal development.