MBTPS2 – Keratosis Follicularis Spinulosa Decalvans

Keratosis follicularis spinulosa decalvans (KFSD) is an X-linked recessive genodermatosis characterized by hyperkeratotic follicular papules, facial erythema, and progressive alopecia. MBTPS2 encodes membrane-bound transcription factor protease site 2 (S2P), a zinc metalloprotease essential for sterol-responsive element-binding protein (SREBP) activation and endoplasmic reticulum stress response. Pathogenic variants in MBTPS2 disrupt SREBP cleavage, leading to abnormal epidermal differentiation and follicular keratinization. Diagnostic confirmation relies on genetic testing of MBTPS2 coupled with functional assays demonstrating impaired protease activity.

Initial linkage and mutation screening in a large Dutch pedigree refined the KFSD locus to Xp22.12–Xp22.11 and identified a recurrent missense variant, c.1523A>G (p.Asn508Ser), in three unrelated families (4 male probands, 5 affected relatives cosegregating) (PMID:20672378). The variant co-segregated with disease and exhibited skewed X-inactivation in symptomatic female carriers, supporting X-linked recessive inheritance. Subsequent British pedigree analysis confirmed the same p.Asn508Ser founder allele in affected males and obligate carriers with facial erythema and hypotrichosis (PMID:22816986). A further child with KFSD was found to carry a novel missense change, c.599C>T (p.Ala200Val), expanding the variant spectrum of MBTPS2 in KFSD (PMID:27663151).

The mutational landscape in KFSD is dominated by missense variants clustering in transmembrane domains of S2P, with a single recurrent founder allele. Intronic splice-site variants have been shown to disrupt normal pre-mRNA processing, as demonstrated for c.225-6T>A and c.671-9T>G in a functional splicing assay (PMID:21426410). Together, at least four distinct MBTPS2 variants (two missense, two splice) have been reported in five unrelated probands with KFSD, with consistent X-linked recessive transmission.

Functional studies of the c.1523A>G (p.Asn508Ser) variant in vitro reveal a 50% reduction in sterol-regulated SREBP activation and impaired cell growth in lipid-depleted media, confirming haploinsufficiency as the primary mechanism (PMID:20672378). Minigene and patient RNA analyses of splice mutants demonstrate exon skipping and premature truncation, corroborating loss of protease function in both missense and intronic mutations. These assays align with the clinical phenotype of follicular hyperkeratosis and alopecia.

No studies dispute the MBTPS2–KFSD association. The consistency of clinical presentation, segregation in multiple pedigrees, and concordant functional impairment across missense and splice variants satisfy strong clinical validity. Additional variants and broader genotype-phenotype correlations have been described but exceed current scoring thresholds.

Key Take-home: X-linked MBTPS2 variants cause KFSD via S2P haploinsufficiency, enabling precise molecular diagnosis for genetic counseling, carrier detection, and future therapeutic targeting.

References

• Human Mutation • 2010 • Keratosis Follicularis Spinulosa Decalvans is caused by mutations in MBTPS2. PMID:20672378
• Clinical and Experimental Dermatology • 2012 • MBTPS2 mutation in a British pedigree with keratosis follicularis spinulosa decalvans. PMID:22816986
• Clinical and Experimental Dermatology • 2016 • Novel MBTPS2 missense mutation causes a keratosis follicularis spinulosa decalvans phenotype: mutation update and review of the literature. PMID:27663151
• Experimental Dermatology • 2011 • Intronic mutations affecting splicing of MBTPS2 cause ichthyosis follicularis, alopecia and photophobia (IFAP) syndrome. PMID:21426410

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