MBTPS2 – BRESHECK syndrome

MBTPS2 (Membrane-Bound Transcription Factor Protease, Site 2; HGNC:15455) is causally associated with BRESHECK syndrome (MONDO:0019414), an X-linked recessive disorder characterized by ichthyosis follicularis, atrichia, photophobia, intellectual disability, and multisystem malformations. Male patients present with the IFAP triad plus brain anomalies, Hirschsprung disease, renal hypoplasia (HP:0000089), and severe hypogammaglobulinemia. The phenotype spectrum overlaps with IFAP and KFSD, reflecting allelic heterogeneity in MBTPS2.

1. Clinical Validity

The gene–disease association is classified as Strong, supported by pathogenic MBTPS2 variants identified in >23 affected males, including 13 unrelated families (PMID:23316014) and multiple case reports with maternal segregation and concordant functional data.

2. Genetic Evidence

Inheritance is X-linked recessive. Segregation analyses demonstrate cosegregation in at least 19 affected male relatives across pedigrees. Key variants include c.1286G>A (p.Arg429His) identified in a severe BRESEK case (PMID:24090718), the recurrent splice-site mutation c.671-9T>G in IFAP/BRESEK (PMID:24313295), and the novel missense c.766G>T (p.Val256Leu) in a BRESHECK patient (PMID:34655156). Multi-patient studies reported 11 different missense variants in 13 families with genotype–phenotype correlations linking mutations near the active site to severe multisystem involvement (PMID:23316014).

3. Functional Evidence

MBTPS2 encodes site-2 protease (S2P), essential for SREBP cleavage and ER stress response. Missense and splice variants impair SREBP activation, reduce cell growth under cholesterol depletion, and disrupt ER stress signaling (PMID:19361614; PMID:21426410). Functional assays in patient-derived cells confirm attenuated sterol-regulated transcription and failure to activate the unfolded protein response, correlating with clinical severity.

4. Mechanism and Conclusion

Pathogenic MBTPS2 variants result in loss-of-function or hypomorphic alleles, leading to impaired lipid homeostasis and ER stress adaptation in skin, neural, and renal tissues. Genotype–phenotype studies and rescue assays provide convergent evidence for a mechanism of protease insufficiency. Additional OI-related findings demonstrate pleiotropic effects of MBTPS2 variants in bone development but exceed the current scope.

Key Take-home: MBTPS2 sequencing should be included in diagnostic panels for X-linked ichthyosis photophobia syndromes to guide management and genetic counseling.

References

• American journal of human genetics • 2009 • IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response. PMID:19361614
• Human mutation • 2010 • Keratosis Follicularis Spinulosa Decalvans is caused by mutations in MBTPS2. PMID:20672378
• Experimental dermatology • 2011 • Intronic mutations affecting splicing of MBTPS2 cause ichthyosis follicularis, alopecia and photophobia (IFAP) syndrome. PMID:21426410
• Human mutation • 2013 • Genotype-phenotype correlations emerging from the identification of missense mutations in MBTPS2. PMID:23316014
• European journal of medical genetics • 2013 • Expanding the phenotype of IFAP/BRESECK syndrome: a new case with severe hypogammaglobulinemia. PMID:24090718
• Clinical and experimental dermatology • 2014 • Recurrent splice-site mutation in MBTPS2 underlying IFAP syndrome with Olmsted syndrome-like features in a Chinese patient. PMID:24313295
• American journal of medical genetics. Part A • 2022 • A novel MBTPS2 variant associated with BRESHECK syndrome impairs sterol-regulated transcription and the endoplasmic reticulum stress response. PMID:34655156

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