FAM111B – Hereditary Fibrosing Poikiloderma with Tendon Contractures and Pulmonary Fibrosis

FAM111B encodes a nuclear trypsin-like serine protease involved in DNA repair, cell cycle regulation, and apoptosis. Heterozygous mutations in FAM111B cause hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) (Gene Symbol; Disease Name).

Autosomal dominant FAM111B variants have been reported in 36 probands from five unrelated families, with segregation observed in each kindred PMID:35122327. Recurrent missense alleles cluster in the predicted protease domain, including c.1247T>C (p.Phe416Ser) in three families PMID:26471370 and c.1861T>G (p.Tyr621Asp) in a sporadic South African patient PMID:36610347.

Clinically, early-onset poikiloderma (HP:0001029), hypotrichosis and hypohidrosis (HP:0000966) occur in >90% of cases, alopecia (HP:0001596) in 86%, myopathy (HP:0003198) in 53%, and adult-onset pulmonary fibrosis (HP:0002206) in 47% of patients with protease-domain mutations PMID:35122327.

Functional assays show that POIKTMP-associated FAM111B mutants hyperactivate protease function, displace key replication and transcription factors from chromatin, and trigger aberrant apoptosis and genomic instability (PMID:32776417; PMID:37342232). Patient fibroblasts harboring c.1861T>G (p.Tyr621Asp) exhibit reduced FAM111B expression, altered nuclear localization, impaired apoptosis, and dysregulated proliferation PMID:36610347.

Integration of genetic segregation, recurrent dominant-negative or gain-of-function alleles, and concordant in vitro dysfunction supports a Strong gene-disease association. Additional studies reinforce a shared protease-driven mechanism with FAM111A mutants, but exceed current ClinGen scoring.

Key Take-Home: FAM111B sequencing is clinically indicated for patients presenting with early-onset poikiloderma, tendon contractures, muscle weakness, and pulmonary fibrosis to enable accurate diagnosis and guide potential targeted interventions.

References

• Experimental Dermatology • 2022 • Mutations within the putative protease domain of the human FAM111B gene may predict disease severity and poor prognosis: A review of POIKTMP cases PMID:35122327
• Orphanet Journal of Rare Diseases • 2015 • Expanding the clinical spectrum of hereditary fibrosing poikiloderma with tendon contractures, myopathy and pulmonary fibrosis due to FAM111B mutations PMID:26471370
• Cancer Treatment and Research Communications • 2023 • FAM111B dysregulation promotes malignancy in fibrosarcoma and POIKTMP and a low-cost method for its mutation screening PMID:36610347
• EMBO Reports • 2020 • FAM111 protease activity undermines cellular fitness and is amplified by gain-of-function mutations in human disease PMID:32776417
• Frontiers in Cell and Developmental Biology • 2023 • Loss of FAM111B protease mutated in hereditary fibrosing poikiloderma negatively regulates telomere length PMID:37342232

Evidence Based Scoring (AI generated)