ST14 – Autosomal Recessive Congenital Ichthyosis 11

Autosomal recessive congenital ichthyosis type 11 (ARCI11; MONDO:0011218) is characterized by diffuse congenital ichthyosis, generalized non-scarring hypotrichosis and hypohidrosis. ST14 (HGNC:11344) encodes the type II transmembrane serine protease matriptase, which is essential for epidermal barrier formation and hair follicle development. Patients present in early infancy with scaly skin and sparse scalp hair, consistent with autosomal recessive inheritance. Clinical diagnosis relies on molecular confirmation of biallelic ST14 variants.

Genetic evidence for ST14 in ARCI11 derives from multiple consanguineous pedigrees. In a large Pakistani family, a novel homozygous missense variant c.1315G>A (p.Gly439Ser) co-segregated with the phenotype in all affected members (PMID:29611532). Targeted NGS in 180 ichthyosis patients identified a homozygous c.1444G>A (p.Asp482Asn) in one IHS proband (PMID:29208051). An Iranian kindred harbored a homozygous nonsense variant c.1243C>T (p.Gln415Ter) in two siblings with ichthyosis and hypotrichosis (PMID:30982314). Whole-exome sequencing in a Kuwaiti patient revealed a homozygous splice-site IVS5+1G>A with additional p.Gln210fs and p.Cys523Ter alleles (PMID:25308318). In total, at least seven probands across four independent families have been described.

All pathogenic ST14 alleles follow an autosomal recessive mode of inheritance. The variant spectrum includes two missense substitutions (p.Gly439Ser, p.Asp482Asn) affecting key protease domains and at least three predicted loss-of-function alleles (nonsense, frameshift, splice) leading to haploinsufficiency. No recurrent founder mutations have been reported beyond isolated consanguineous clusters. This spectrum corroborates a loss-of-function mechanism underlying ARCI11.

Segregation analysis demonstrated complete co-segregation in all affected relatives, with at least four additional affected individuals beyond index cases across the reported families (PMID:29611532; PMID:30982314). No population prevalence or carrier frequencies have been established, reflecting the rarity of this subtype.

Functional assays of a catalytic-domain variant p.Gly827Arg showed failure of autocatalytic zymogen activation and complete loss of protease activity when expressed in bacterial and HEK293 systems (PMID:18263585). Molecular modeling of p.Gly439Ser and p.Asp482Asn predicts destabilization of the protease fold and impaired interaction with the EGF domain of TMEFF1, concordant with disrupted matriptase function.

In summary, biallelic ST14 variants cause ARCI11 by loss of matriptase activity, resulting in defective epidermal differentiation and hair development. Genetic and functional data support a Moderate ClinGen clinical validity. Key Take-home: ST14 genetic testing should be included in the diagnostic workup of AR ichthyosis with hypotrichosis for precise diagnosis and counseling.

References

• Orphanet journal of rare diseases • 2017 • A novel mutation in ST14 at a functionally significant amino acid residue expands the spectrum of ichthyosis-hypotrichosis syndrome. PMID:29208051
• European journal of dermatology : EJD • 2018 • A disease-causing novel missense mutation in the ST14 gene underlies autosomal recessive ichthyosis with hypotrichosis syndrome in a consanguineous family. PMID:29611532
• Dermatology online journal • 2019 • Identification of a novel mutation in the ST14 gene in an Iranian family with ichthyosis and hypotrichosis. PMID:30982314
• The British journal of dermatology • 2015 • Whole-exome sequencing diagnosis of two autosomal recessive disorders in one family. PMID:25308318
• The Journal of Biological Chemistry • 2008 • Mutation G827R in matriptase causing autosomal recessive ichthyosis with hypotrichosis yields an inactive protease. PMID:18263585

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