KCTD1 – Scalp-Ear-Nipple Syndrome

KCTD1 encodes a BTB-domain transcriptional repressor and is associated with autosomal dominant scalp-ear-nipple (SEN) syndrome, an ectodermal dysplasia characterized by cutis aplasia of the scalp, external ear anomalies, and hypoplastic breasts. The inheritance pattern is autosomal dominant with high penetrance. To date, 25 probands in 12 unrelated families have been reported with heterozygous KCTD1 missense variants causing SEN syndrome (15 PMID:36579937; 10 PMID:23541344).

Initial exome sequencing of a multiplex pedigree identified ten distinct KCTD1 missense mutations clustering in the conserved BTB domain, all segregating with disease. A representative variant, c.1913C>A (p.Ala638Glu), abolishes transcriptional repressor activity and was found in one family (PMID:23541344). These variants define a clear allelic spectrum of pathogenic missense changes in SEN syndrome.

A follow-up multi-family study described 15 affected members from two pedigrees carrying recurrent p.(Ala30Glu) or p.(Pro31Leu) variants. All individuals exhibited scalp defects, prominent ears, rudimentary breasts, and 5/6 examined had low myopic astigmatism; one had divergent strabismus. Five also showed renal cysts with thin glomerular basement membranes akin to thin basement membrane nephropathy (PMID:36579937).

Beyond ectodermal features, recurrent p.(Ala30Glu) in 12 individuals suggests a founder effect in one pedigree. The variant spectrum comprises exclusively missense changes within key structural elements of the BTB and pre-BTB regions that are critical for KCTD1 homomeric assembly and transcriptional repression.

Functional assays demonstrate that SEN-associated mutants fail to bind transcription factor AP-2α, leading to dysregulated Wnt/β-catenin signaling. Mutants exhibit significant BTB domain destabilization and form aggregation-prone species (PMID:31324836; PMID:33000225). Structural analysis uncovered an unrecognized BTB extension and ion-binding channel that mediate TFAP2A interaction; the P20S disease variant maps to this region (PMID:39191250).

Animal models further corroborate human phenotypes: TFAP2B and COL4A3/4 knockout mice develop renal cysts and myopia respectively, mirroring patient comorbidities (PMID:36579937). Kctd1 I27N heterozygous mice exhibit kidney dysfunction without overt ectodermal defects, underscoring KCTD1’s role in renal physiology (PMID:28818080).

Collectively, the genetic and experimental data fulfill ClinGen criteria for a Strong gene–disease association. Dominant-negative KCTD1 missense variants disrupt BTB domain–mediated transcriptional repression, yielding a consistent ectodermal and renal phenotype. Clinical screening of KCTD1 variants is warranted for definitive SEN diagnosis and management of ocular/renal comorbidities.

References

• Ophthalmic genetics • 2023 • KCTD1 and Scalp-Ear-Nipple (‘Finlay-Marks’) syndrome may be associated with myopia and Thin basement membrane nephropathy through an effect on the collagen IV α3 and α4 chain PMID:36579937
• American journal of human genetics • 2013 • Mutations in KCTD1 cause scalp-ear-nipple syndrome PMID:23541344
• Scientific reports • 2019 • Molecular basis of the scalp-ear-nipple syndrome unraveled by the characterization of disease-causing KCTD1 mutants PMID:31324836
• Molecular medicine reports • 2020 • KCTD1 mutants in scalp-ear-nipple syndrome and AP-2α P59A in Char syndrome reciprocally abrogate their interactions, but can regulate Wnt/β-catenin PMID:33000225
• Structure • 2024 • A BTB extension and ion-binding domain contribute to the pentameric structure and TFAP2A binding of KCTD1 PMID:39191250
• Journal of biomedical science • 2017 • Standardized, systemic phenotypic analysis reveals kidney dysfunction as main alteration of Kctd1 I27N mutant mice PMID:28818080

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