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

Orphanet Journal of Rare Diseases

Mustafa Tekin⁸  Steffen Thiel⁹  Hulya Kayserili⁵  Yasemin Alanay^1,10  Ferda Ozkinay²  Mustafa Ozen⁴  Sevinc Sahin Atik^1,11  Gulsen A. Tayfun⁷  Nursel Elcioglu⁷  Sarah Bowdin¹  Gül Yesiltepe Mutlu³  Umut Altunoglu⁵  Joseph Foster⁸  Guney Bademci⁸  Asuman Koparir⁶  Tahir Atik² 

[1] Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada;Division of Genetics, Department of Pediatrics, Ege University School of Medicine, Izmir, Turkey;Division of Pediatric Endocrinology and Diabetes, Kocaeli University School of Medicine, Kocaeli, Turkey;Department of Medical Genetics/Molecular Biology and Genetics Biruni University, Istanbul, Turkey;Department of Medical Genetics, Istanbul Medical School, Istanbul University, Istanbul, Turkey;Department of Medical Genetics, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey;Division of Genetics, Department of Pediatrics, Marmara University School of Medicine, Istanbul, Turkey;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 33136, FL, USA;Department of Biomedicine, Aarhus University, Aarhus, Denmark;Division of Genetics, Department of Pediatrics, Acibadem University Medical Faculty, Istanbul, Turkey;Department of Ophthalmology, Ataturk Teaching and Research Hospital, Katip Celebi University, Izmir, Turkey

关键词: MASP-3;    MASP-1;    Lectin pathway;    Complement;    3MC syndrome;   

Others  :  1228432
DOI  :  10.1186/s13023-015-0345-3

 received in 2015-07-08, accepted in 2015-09-23,  发布年份 2015

【 摘 要 】

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.

Conclusion

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.

【 授权许可】

   
2015 Atik et al.

【 图 表 】

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