MASP1 Mutations in Patients with Facial, Umbilical, Coccygeal, and Auditory Findings of Carnevale, Malpuech, OSA, and Michels Syndromes

Abstract

Distinctive facial features consisting of hypertelorism, telecanthus, blepharophimosis, blepharoptosis, epicanthus inversus, periumbilical defects, and skeletal anomalies are seen in autosomal-recessive Carnevale, Malpuech, Michels, and oculo-skeletal-abdominal (OSA) syndromes. The gene or genes responsible for these syndromes were heretofore unknown. We report on three individuals from two consanguineous Turkish families with findings characteristic of these syndromes, including facial dysmorphism, periumbilical depression, mixed hearing loss, radioulnar synostosis, and coccygeal appendage. Homozygosity mapping yielded an autozygous region on chromosome 3q27 in both families. In one family, whole exome sequencing revealed a missense mutation, MASP1 c.2059G>A (p.G687R), that cosegregated with the phenotype. In the second family, Sanger sequencing of MASP1 revealed a nonsense mutation, MASP1 c.870G>A (p.W290X), that also cosegregated with the phenotype. Neither mutation was found in 192 Turkish controls or 1200 controls of various other ancestries. MASP1 encodes mannan-binding lectin serine protease 1. The two mutations occur in a MASP1 isoform that has been reported to process IGFBP-5, thereby playing a critical role in insulin growth factor availability during craniofacial and muscle development. These results implicate mutations of MASP1 as the cause of a human malformation syndrome and demonstrate the involvement of MASP1 in facial, umbilical, and ear development during the embryonic period.

Mannan-Binding Lectin-Associated Serine Protease (MASP)-1 Is Crucial for Lectin Pathway Activation in Human Serum, whereas neither MASP-1 nor MASP-3 Is Required for Alternative Pathway Function

“…The index patient was a girl aged 9 with normal growth and normal early neurodevelopment, but having mild mental retardation and craniofacial and midline defects consistent with 3MC syndrome, as previously described in detail (18). She had only one infection, of the urinary tract, severe enough to require hospitalization.…”

“…The common denominator of causative MASP1 gene defects is the absence of a functional form of MASP-3, but in one individual a nonsense mutation was localized to the part of MASP1 encoding the common domains of MASP-1, MASP-3, and MAp44, most likely conferring a complete deficiency of these proteins in the homozygous state ( Fig. 1) (18). In this study, we prove the deficiency of all three proteins and use clinical material from this patient to analyze the consequences for complement functionality.…”

“…Genetic studies recently revealed that mutations in MASP1 and COLEC11 underlie the etiology of 3MC syndrome (16), a rare autosomal recessive disorder characterized by facial dysmorphism, short stature, intellectual disability, midline defects, and caudal appendage (17,18). The common denominator of causative MASP1 gene defects is the absence of a functional form of MASP-3, but in one individual a nonsense mutation was localized to the part of MASP1 encoding the common domains of MASP-1, MASP-3, and MAp44, most likely conferring a complete deficiency of these proteins in the homozygous state ( Fig.…”

Lectin pathway of complement activation and relation with clinical complications in critically ill children

“…Recombinant MASP-3 has some activity on insulin-like growth factor-binding protein-5 and some synthetic substrates (27). A critical role of MASP-3 in insulin-like growth factor-binding protein-5 availability during craniofacial, muscle, and neural crest development was suggested based on specific mutations (28)(29)(30). In mice, MASP-1 and MASP-3 play a role in the alternative pathway of complement activation and thus might act as a backup system when the lectin pathway is deficient (31).…”

Next-generation sequencing: impact of exome sequencing in characterizing Mendelian disorders

“…Shared homozygous or compound heterozygous variants are used to find the candidate variant (Figures 2a1 and a2). In a study by Sirmaci et al, 47 the cause of MalpuechMichels-Mingarelli-Carnevale syndrome in two affected families was identified. An autozygous region on chromosome 3q.27 was identified and exome sequencing confirmed MASP1 mutation co-segregated with the phenotype.…”