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Heterozygous missense variants in the closely related paralogue KCTD1 cause scalp-ear-nipple syndrome.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>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 <jats:italic>KCTD15<\/jats:italic> 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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>A heterozygous c.310G&gt;C variant encoding p.(Asp104His) within the BTB domain of <jats:italic>KCTD15<\/jats:italic> was identified in an affected father and daughter and segregated with the phenotype. In the sporadically affected patient, a de novo heterozygous c.263G&gt;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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg-2023-109531","type":"journal-article","created":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T13:30:44Z","timestamp":1706707844000},"page":"490-501","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":11,"title":["BTB domain mutations perturbing KCTD15 oligomerisation cause a distinctive frontonasal dysplasia syndrome"],"prefix":"10.1136","volume":"61","author":[{"given":"Kerry A","family":"Miller","sequence":"first","affiliation":[{"name":"MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A","family":"Cruz Walma","sequence":"additional","affiliation":[{"name":"Centre for Medicines Discovery, 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