MASP1 – 3MC Syndrome

3MC syndrome is a rare autosomal recessive disorder characterized by distinctive craniofacial dysmorphism, cleft lip and/or palate, blepharophimosis, hypertelorism, craniosynostosis, genital and limb anomalies. Biallelic pathogenic variants in MASP1, encoding the complement lectin pathway proteases MASP-1 and MASP-3, underlie the syndrome. Clinical presentations range from classical facial gestalt to hearing loss, growth delay, and neurodevelopmental comorbidities. Recognition of MASP1 mutations is critical for accurate diagnosis, genetic counseling, and management of multisystem involvement.

Genetic evidence supporting MASP1–3MC syndrome is robust. In a landmark study of 11 families, biallelic MASP1 variants were identified in affected individuals with segregation in consanguineous kindreds ([PMID:21258343]). A subsequent cohort of 27 patients from 22 families carrying homozygous or compound heterozygous MASP1 variants further confirmed autosomal recessive inheritance and case-level replication across multiple populations ([PMID:34899147]). Segregation analysis in two unrelated consanguineous families demonstrated four additional affected siblings inheriting homozygous MASP1 deletions or splice variants ([PMID:27356087]). Representative variants span intronic splice sites, missense substitutions, and frameshift alleles, exemplified by c.744+1G>A (splice donor) in MASP1.

The variant spectrum in MASP1 includes at least 16 distinct alleles: intronic splice mutations (e.g., c.744+1G>A), exon deletions, missense changes affecting the serine protease domain, and frameshifts disrupting MASP-3-specific exons. Both loss-of-function and missense alleles segregate with the phenotype, with no apparent founder effect but frequent recurrence in consanguineous cohorts. Carrier frequencies remain undefined, reflecting rarity; no population-specific founder has been conclusively described.

Functional studies demonstrate that MASP-3 is essential for maturation of complement factor D (pro-FD) and guidance of neural crest cells. MASP1/3-deficient zebrafish morphants develop severe craniofacial defects mirroring human 3MC syndrome, and Masp1/3 knockout mice show impaired pro-FD conversion and attenuated alternative pathway activity ([PMID:21258343]). Structural and enzymatic analyses of MASP-3 G666E and related mutants reveal complete loss of catalytic activity and disruption of the active site architecture ([PMID:23792966]). These data confirm that MASP-3 dysfunction abrogates its maturase role and perturbs complement-mediated developmental signaling.

Together, genetic and experimental findings establish MASP1 as definitively associated with 3MC syndrome. The autosomal recessive inheritance pattern, segregation in multiple families, extensive variant spectrum, and concordant animal and biochemical models fulfill ClinGen criteria for a Definitive gene–disease relationship. MASP1 mutation screening should be incorporated into diagnostic panels for craniofacial and multisystem developmental disorders. Key Take-home: Biallelic MASP1 variants cause 3MC syndrome via loss of MASP-3 maturase activity, with clear diagnostic, prognostic, and genetic counseling implications.

References

• Nature genetics • 2011 • Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome. PMID:21258343
• Molecular syndromology • 2021 • Further Expansion of the Mutational Spectrum of 3MC Syndrome: A Novel MASP1 Pathogenic Variant in a Male Patient. PMID:34899147
• The Cleft palate-craniofacial journal • 2017 • Familial Recurrence of 3MC Syndrome in Consanguineous Families: A Clinical and Molecular Diagnostic Approach With Review of the Literature. PMID:27356087
• The Journal of biological chemistry • 2013 • The x-ray crystal structure of mannose-binding lectin-associated serine proteinase-3 reveals the structural basis for enzyme inactivity associated with the Carnevale, Mingarelli, Malpuech, and Michels (3MC) syndrome. PMID:23792966

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