title: Novel MASP1 mutations are associated with an expanded phenotype in 3MC1 syndrome.
abstract: BACKGROUND
  3MC1 syndrome is a rare autosomal recessive disorder characterized by intellectual disability, short stature and distinct craniofacial, umbilical, and sacral anomalies. Five mutations in MASP1, encoding lectin complement pathway enzymes MASP-1 and MASP-3, have thus far been reported to cause 3MC1 syndrome. Only one previously reported mutation affects both MASP-1 and MASP-3, while the other mutations affect only MASP-3.
  
  
  METHODS
  We evaluated six unrelated individuals with 3MC1 syndrome and performed Sanger sequencing for all coding exons of MASP1. We also measured complement lectin and alternative pathway activities in an affected individual's serum.
  
  
  RESULTS
  We found two novel splice site mutations, c.1012-2A > G in one and c.891 + 1G > T in two probands, and three novel missense mutations, c.1451G > A (p.G484E), c.1657G > A (p.D553N), and c.1987G > T (p.D663Y). Missense mutations affect only MASP-3, while splice site mutations affect both MASP-1 and MASP-3. In a proband who is homozygous for c.891 + 1G > T, we detected a total lack of lectin complement pathway activity and a 2.5-fold lower alternative pathway activity. The phenotype observed in patients whose both MASP-1 and MASP-3 are affected and in those whose only MASP-3 is affected does not appear to be different. We observed structural brain abnormalities, neonatal tooth, a vascular anomaly and a solid lesion in liver as novel phenotypic features of 3MC1 syndrome.
  
  
  CONCLUSIONS
  Novel mutations and additional phenotypic features expand the genotypic and phenotypic spectrum of 3MC1 syndrome. Although patients with MASP-1 dysfunction in addition to disrupted MASP-3 have an altered complement system, their disease phenotype is not different from those having only MASP-3 dysfunction.
authors.affiliation: Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, 1501 NW 10th Avenue, BRB-610 M-860, Miami, FL, 33136, USA. tahiratik@yahoo.com.|Division of Genetics, Department of Pediatrics, Ege University School of Medicine, Izmir, Turkey. tahiratik@yahoo.com.
authors.forename: Tahir
authors.initials: T
authors.lastname: Atik
authors.affiliation: Department of Medical Genetics, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey. asumanpayas@yahoo.com.
authors.forename: Asuman
authors.initials: A
authors.lastname: Koparir
authors.affiliation: Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, 1501 NW 10th Avenue, BRB-610 M-860, Miami, FL, 33136, USA. g.bademci@med.miami.edu.
authors.forename: Guney
authors.initials: G
authors.lastname: Bademci
authors.affiliation: Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, 1501 NW 10th Avenue, BRB-610 M-860, Miami, FL, 33136, USA. jfoster2@med.miami.edu.
authors.forename: Joseph
authors.initials: J
authors.lastname: Foster
authors.affiliation: Department of Medical Genetics, Istanbul Medical School, Istanbul University, Istanbul, Turkey. ualtunoglu@gmail.com.
authors.forename: Umut
authors.initials: U
authors.lastname: Altunoglu
authors.affiliation: Division of Pediatric Endocrinology and Diabetes, Kocaeli University School of Medicine, Kocaeli, Turkey. gulyesiltepe@gmail.com.
authors.forename: Gül Yesiltepe
authors.initials: GY
authors.lastname: Mutlu
authors.affiliation: Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada. sarah.bowdin@sickkids.ca.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bowdin
authors.affiliation: Division of Genetics, Department of Pediatrics, Marmara University School of Medicine, Istanbul, Turkey. nelcioglu@yahoo.com.
authors.forename: Nursel
authors.initials: N
authors.lastname: Elcioglu
authors.affiliation: Division of Genetics, Department of Pediatrics, Marmara University School of Medicine, Istanbul, Turkey. drglsenakay@yahoo.com.
authors.forename: Gulsen A
authors.initials: GA
authors.lastname: Tayfun
authors.affiliation: Department of Ophthalmology, Ataturk Teaching and Research Hospital, Katip Celebi University, Izmir, Turkey. drsevincsahin@yahoo.com.
authors.forename: Sevinc Sahin
authors.initials: SS
authors.lastname: Atik
authors.affiliation: Department of Medical Genetics, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey. meozen@gmail.com.|Department of Medical Genetics/Molecular Biology and Genetics Biruni University, Istanbul, Turkey. meozen@gmail.com.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Ozen
authors.affiliation: Division of Genetics, Department of Pediatrics, Ege University School of Medicine, Izmir, Turkey. f.ferda.ozkinay@ege.edu.tr.
authors.forename: Ferda
authors.initials: F
authors.lastname: Ozkinay
authors.affiliation: Division of Genetics, Department of Pediatrics, Acibadem University Medical Faculty, Istanbul, Turkey. yasemin.alanay@acibadem.edu.tr.
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Alanay
authors.affiliation: Department of Medical Genetics, Istanbul Medical School, Istanbul University, Istanbul, Turkey. hkayserili@ku.edu.tr.|Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey. hkayserili@ku.edu.tr.
authors.forename: Hulya
authors.initials: H
authors.lastname: Kayserili
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark. st@biomed.au.dk.
authors.forename: Steffen
authors.initials: S
authors.lastname: Thiel
authors.affiliation: Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, 1501 NW 10th Avenue, BRB-610 M-860, Miami, FL, 33136, USA. mtekin@miami.edu.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Tekin
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000235:genetics*; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D050606:Mannose-Binding Protein-Associated Serine Proteases / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D013577:Syndrome; D055815:Young Adult
chemical_list: C084067:MASP1 protein, human; D050606:Mannose-Binding Protein-Associated Serine Proteases