MBTPS2 – Ichthyosis Follicularis, Atrichia and Photophobia Syndrome

Ichthyosis follicularis, atrichia, and photophobia (IFAP) syndrome is a rare X-linked recessive genodermatosis characterized by follicular ichthyosis, congenital atrichia, and severe photophobia. Pathogenic variants in the membrane-bound transcription factor protease, site 2 (MBTPS2) underlie this condition, disrupting sterol-regulated transcription and endoplasmic reticulum (ER) stress response (PMID:19361614). IFAP syndrome predominantly affects hemizygous males, with carrier females typically asymptomatic or mildly affected.

Genetic evidence includes a large five-generation Chinese pedigree exhibiting cosegregation of a novel MBTPS2 missense mutation with the disease phenotype in 12 affected individuals (PMID:21315478). To date, over 40 unrelated IFAP cases have been reported worldwide (PMID:28654459), encompassing multiple ethnicities. Segregation analysis in these families and the presence of hemizygous variants exclusively in affected males support an X-linked recessive inheritance model.

The variant spectrum comprises predominantly missense substitutions and critical intronic alterations leading to aberrant splicing. At least 25 distinct MBTPS2 variants have been described, including c.245T>C (p.Phe82Ser) in a 7-year-old boy with classic IFAP triad and mild extracutaneous features (PMID:35221597). Additional splice-site mutations, such as c.225-6T>A, cause exon extension and premature truncation, as demonstrated by in vitro minigene assays (PMID:21426410).

Functional studies reveal that IFAP-associated MBTPS2 variants impair SREBP cleavage and attenuate the ER stress response. Missense mutations exchange conserved residues in the active site, reducing proteolytic activity and correlating quantitatively with clinical severity (PMID:19361614). Splice-site defects abolish proper mRNA processing, further compromising protease function and cholesterol homeostasis.

No studies to date have refuted the MBTPS2–IFAP association or reported asymptomatic hemizygotes carrying loss-of-function alleles. The consistent phenotype across diverse cohorts and concordant experimental data underscore the gene–disease relationship.

In summary, MBTPS2 variants produce a definitive X-linked recessive IFAP syndrome through haploinsufficiency of site-2 protease activity. Genetic testing for MBTPS2 mutations enables accurate diagnosis, informs carrier detection, and guides tailored ocular and dermatological management. Key Take-home: MBTPS2 sequencing should be considered in males presenting with the IFAP triad to enable early intervention 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
• Journal of the American Academy of Dermatology • 2011 • A novel mutation in MBTPS2 causes a broad phenotypic spectrum of ichthyosis follicularis, atrichia, and photophobia syndrome in a large Chinese family. PMID:21315478
• Experimental Dermatology • 2011 • Intronic mutations affecting splicing of MBTPS2 cause ichthyosis follicularis, alopecia and photophobia (IFAP) syndrome. PMID:21426410
• Journal of Pediatric Hematology/Oncology • 2018 • Hodgkin Lymphoma in a Patient With IFAP Syndrome: A Case Report and Review of Literature. PMID:28654459
• Annals of Dermatology • 2022 • A Novel Mutation in the MBTPS2 Gene Resulting in Ichthyosis Follicularis, Atrichia, and Photophobia Syndrome. PMID:35221597

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