RSPO4 – Nonsyndromic Congenital Nail Disorder 4

Biallelic loss-of-function variants in RSPO4 cause autosomal recessive nonsyndromic congenital nail disorder 4, characterized by congenital absence of all finger- and toenails (anonychia). Initial linkage in a large German pedigree mapped disease to 20p13 and identified a frameshift (c.145_166dup (p.Leu56fs)) and a nonconservative missense (c.218G>A (p.Cys73Tyr)) variant in exon 2 segregating with phenotype in four affected siblings in an autosomal recessive pattern (3 additional affected relatives) (PMID:17186469).

Subsequent reports expanded the allelic series, including a novel nonsense variant c.164_165delinsAA (p.Ser55Ter) in a Lebanese individual with congenital anonychia (1 proband) (PMID:28247548) and two more variants, c.190C>T (p.Arg64Cys) and c.301C>T (p.Gln101Ter), identified in additional affected individuals (PMID:17914448).

To date, at least six pathogenic RSPO4 variants—four frameshift/stop and two missense—have been found in seven affected individuals from two unrelated pedigrees, consistently showing autosomal recessive inheritance and complete penetrance (PMID:17186469; PMID:28247548; PMID:17914448).

Functional studies reveal that RSPO4 variants cluster in the furin-like cysteine-rich domains critical for Wnt/β-catenin signaling activation. In vitro assays show that mutant proteins fail to amplify Wnt3A-induced signaling and cannot antagonize DKK1-mediated LRP6 inhibition, confirming a loss-of-function mechanism (PMID:18400942).

Integration of genetic segregation data and concordant functional assays provides a Strong level of clinical validity for RSPO4 in nonsyndromic congenital nail disorder 4. Further studies, including animal models, may deepen mechanistic insights.

Key Take-home: RSPO4 genetic testing enables definitive diagnosis and carrier screening for congenital anonychia with implications for genetic counseling and potential Wnt-targeted therapies.

References

• Clinical and experimental dermatology | 2017 | A novel mutation in the RSPO4 gene in a patient with autosomal recessive anonychia. PMID:28247548
• American journal of human genetics | 2006 | Mutations in the gene encoding the Wnt-signaling component R-spondin 4 (RSPO4) cause autosomal recessive anonychia. PMID:17186469
• The Journal of investigative dermatology | 2008 | RSPO4 is the major gene in autosomal-recessive anonychia and mutations cluster in the furin-like cysteine-rich domains of the Wnt signaling ligand R-spondin 4. PMID:17914448
• Molecular biology of the cell | 2008 | R-Spondin family members regulate the Wnt pathway by a common mechanism. PMID:18400942

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