%0 Journal Article
%T BTB domain mutations perturbing KCTD15 oligomerisation cause a distinctive frontonasal dysplasia syndrome.
%A Miller KA
%A Cruz Walma DA
%A Pinkas DM
%A Tooze RS
%A Bufton JC
%A Richardson W
%A Manning CE
%A Hunt AE
%A Cros J
%A Hartill V
%A Parker MJ
%A McGowan SJ
%A Twigg SRF
%A Chalk R
%A Staunton D
%A Johnson D
%A Wilkie AOM
%A Bullock AN
%J J Med Genet
%V 61
%N 5
%D 2024 Apr 19
%M 38296633
%F 5.941
%R 10.1136/jmg-2023-109531
%X <B>BACKGROUND: </B>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.<BR><B>METHODS: </B>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.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>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.