BTB domain mutations perturbing KCTD15 oligomerisation cause a distinctive frontonasal dysplasia syndrome.
In: Journal of medical genetics, Jg. 61 (2024-04-19), Heft 5, S. 490-501
academicJournal
Zugriff:
Introduction: 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.
Conclusion: 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.
Competing Interests: Competing interests: None declared.
(© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)
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BTB domain mutations perturbing KCTD15 oligomerisation cause a distinctive frontonasal dysplasia syndrome.
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Autor/in / Beteiligte Person: | Miller, KA ; Cruz Walma, DA ; Pinkas, DM ; Tooze, RS ; Bufton, JC ; Richardson, W ; Manning, CE ; Hunt, AE ; Cros, J ; Hartill, V ; Parker, MJ ; McGowan, SJ ; Twigg, SRF ; Chalk, R ; Staunton, D ; Johnson, D ; Wilkie, AOM ; Bullock, AN |
Zeitschrift: | Journal of medical genetics, Jg. 61 (2024-04-19), Heft 5, S. 490-501 |
Veröffentlichung: | London : British Medical Association, 2024 |
Medientyp: | academicJournal |
ISSN: | 1468-6244 (electronic) |
DOI: | 10.1136/jmg-2023-109531 |
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