Novel MASP1 mutations are associated with an expanded phenotype in 3MC1 syndrome

Orphanet Journal of Rare Diseases - Tập 10 - Trang 1-10 - 2015
Tahir Atik1,2, Asuman Koparir3, Guney Bademci1, Joseph Foster1, Umut Altunoglu4, Gül Yesiltepe Mutlu5, Sarah Bowdin6, Nursel Elcioglu7, Gulsen A. Tayfun7, Sevinc Sahin Atik8, Mustafa Ozen3,9, Ferda Ozkinay2, Yasemin Alanay10, Hulya Kayserili4,11, Steffen Thiel12, Mustafa Tekin1
1Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, USA
2Division of Genetics, Department of Pediatrics, Ege University School of Medicine, Izmir, Turkey
3Department of Medical Genetics, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
4Department of Medical Genetics, Istanbul Medical School, Istanbul University, Istanbul, Turkey
5Division of Pediatric Endocrinology and Diabetes, Kocaeli University School of Medicine, Kocaeli, Turkey
6Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, Toronto, Canada
7Division of Genetics, Department of Pediatrics, Marmara University School of Medicine, Istanbul, Turkey
8Department of Ophthalmology, Ataturk Teaching and Research Hospital, Katip Celebi University, Izmir, Turkey
9Department of Medical Genetics/Molecular Biology and Genetics Biruni University, Istanbul, Turkey
10Division of Genetics, Department of Pediatrics, Acibadem University Medical Faculty, Istanbul, Turkey
11Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey
12Department of Biomedicine, Aarhus University, Aarhus, Denmark

Tóm tắt

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. 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. 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. 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.

Tài liệu tham khảo

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Orphanet Journal of Rare Diseases

Tập 10

1-10

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