PDF(Pubmed)
Abstract：
BACKGROUND: KCTD15 encodes an oligomeric BTB domain protein reported to inhibit neural crest formation through repression of Wnt/beta-catenin signalling, as well as transactivation by TFAP2. Heterozygous missense variants in the closely related paralogue KCTD1 cause scalp-ear-nipple syndrome.
METHODS: Exome sequencing was performed on a two-generation family affected by a distinctive phenotype comprising a lipomatous frontonasal malformation, anosmia, cutis aplasia of the scalp and/or sparse hair, and congenital heart disease. Identification of a de novo missense substitution within KCTD15 led to targeted sequencing of DNA from a similarly affected sporadic patient, revealing a different missense mutation. Structural and biophysical analyses were performed to assess the effects of both amino acid substitutions on the KCTD15 protein.
RESULTS: A heterozygous c.310G>C variant encoding p.(Asp104His) within the BTB domain of KCTD15 was identified in an affected father and daughter and segregated with the phenotype. In the sporadically affected patient, a de novo heterozygous c.263G>A variant encoding p.(Gly88Asp) was present in KCTD15. Both substitutions were found to perturb the pentameric assembly of the BTB domain. A crystal structure of the BTB domain variant p.(Gly88Asp) revealed a closed hexameric assembly, whereas biophysical analyses showed that the p.(Asp104His) substitution resulted in a monomeric BTB domain likely to be partially unfolded at physiological temperatures.
CONCLUSIONS: BTB domain substitutions in KCTD1 and KCTD15 cause clinically overlapping phenotypes involving craniofacial abnormalities and cutis aplasia. The structural analyses demonstrate that missense substitutions act through a dominant negative mechanism by disrupting the higher order structure of the KCTD15 protein complex.
METHODS: Exome sequencing was performed on a two-generation family affected by a distinctive phenotype comprising a lipomatous frontonasal malformation, anosmia, cutis aplasia of the scalp and/or sparse hair, and congenital heart disease. Identification of a de novo missense substitution within KCTD15 led to targeted sequencing of DNA from a similarly affected sporadic patient, revealing a different missense mutation. Structural and biophysical analyses were performed to assess the effects of both amino acid substitutions on the KCTD15 protein.
RESULTS: A heterozygous c.310G>C variant encoding p.(Asp104His) within the BTB domain of KCTD15 was identified in an affected father and daughter and segregated with the phenotype. In the sporadically affected patient, a de novo heterozygous c.263G>A variant encoding p.(Gly88Asp) was present in KCTD15. Both substitutions were found to perturb the pentameric assembly of the BTB domain. A crystal structure of the BTB domain variant p.(Gly88Asp) revealed a closed hexameric assembly, whereas biophysical analyses showed that the p.(Asp104His) substitution resulted in a monomeric BTB domain likely to be partially unfolded at physiological temperatures.
CONCLUSIONS: BTB domain substitutions in KCTD1 and KCTD15 cause clinically overlapping phenotypes involving craniofacial abnormalities and cutis aplasia. The structural analyses demonstrate that missense substitutions act through a dominant negative mechanism by disrupting the higher order structure of the KCTD15 protein complex.
摘要：
背景：KCTD15编码寡聚BTB结构域蛋白，据报道通过抑制Wnt/β-catenin信号传导来抑制神经c形成，以及TFAP2的反式激活。密切相关旁系物KCTD1中的杂合错义变异导致头皮-耳-乳头综合征
方法：对一个两代家族进行外显子组测序，该家族受一种独特的表型影响，该表型包括脂肪瘤状额鼻部畸形，嗅觉缺失,头皮角化生和/或稀疏的头发，先天性心脏病.KCTD15中从头错义替换的鉴定导致对类似受影响的散发性患者的DNA进行靶向测序，揭示了一个不同的错义突变。进行结构和生物物理分析以评估两种氨基酸取代对KCTD15蛋白的影响。
结果:在受影响的父亲和女儿中鉴定出编码KCTD15的BTB结构域内的p.(Asp104His)的杂合c.310G>C变体,并与表型分离。在偶尔受影响的患者中，从头杂合c.263G>KCTD15中存在编码p.(Gly88Asp)的变体。发现两种取代都扰乱BTB结构域的五聚体组装。BTB结构域变体p的晶体结构。（Gly88Asp）揭示了封闭的六聚体组装，而生物物理分析显示p.(Asp104His)取代导致单体BTB结构域可能在生理温度下部分展开。
结论：KCTD1和KCTD15中的BTB结构域替换导致临床上重叠的表型，包括颅面畸形和角体发育。结构分析表明，错义取代通过破坏KCTD15蛋白质复合物的高级结构而通过显性负机制起作用。
方法：对一个两代家族进行外显子组测序，该家族受一种独特的表型影响，该表型包括脂肪瘤状额鼻部畸形，嗅觉缺失,头皮角化生和/或稀疏的头发，先天性心脏病.KCTD15中从头错义替换的鉴定导致对类似受影响的散发性患者的DNA进行靶向测序，揭示了一个不同的错义突变。进行结构和生物物理分析以评估两种氨基酸取代对KCTD15蛋白的影响。
结果:在受影响的父亲和女儿中鉴定出编码KCTD15的BTB结构域内的p.(Asp104His)的杂合c.310G>C变体,并与表型分离。在偶尔受影响的患者中，从头杂合c.263G>KCTD15中存在编码p.(Gly88Asp)的变体。发现两种取代都扰乱BTB结构域的五聚体组装。BTB结构域变体p的晶体结构。（Gly88Asp）揭示了封闭的六聚体组装，而生物物理分析显示p.(Asp104His)取代导致单体BTB结构域可能在生理温度下部分展开。
结论：KCTD1和KCTD15中的BTB结构域替换导致临床上重叠的表型，包括颅面畸形和角体发育。结构分析表明，错义取代通过破坏KCTD15蛋白质复合物的高级结构而通过显性负机制起作用。
