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

Atik T, Koparir A, Bademci G, Foster J, Altunoglu U, Mutlu GY, Bowdin S, Elcioglu N, Tayfun GA, Atik SS, Ozen M, Ozkinay F, Alanay Y, Kayserili H, Thiel S, Tekin M - Orphanet J Rare Dis (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

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.

No MeSH data available.


Related in: MedlinePlus

a Overview of MASP1 mutations. Exons and introns are indicated by circles with numbers and thin lines, respectively. The localization of mutations identified in this study is shown with blue arrows; those reported by Sirmaci et al.[3] and Rooryck et al. [4] are shown with red arrows; b Overview of the resulting protein structures of the three mRNA sequences produced from MASP1. In protein domains of these different transcripts, the blue arrows and red arrows show the mutations presented in this study and reported previously, respectively [3, 4]
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Fig1: a Overview of MASP1 mutations. Exons and introns are indicated by circles with numbers and thin lines, respectively. The localization of mutations identified in this study is shown with blue arrows; those reported by Sirmaci et al.[3] and Rooryck et al. [4] are shown with red arrows; b Overview of the resulting protein structures of the three mRNA sequences produced from MASP1. In protein domains of these different transcripts, the blue arrows and red arrows show the mutations presented in this study and reported previously, respectively [3, 4]

Mentions: Mutations in two genes, MASP1 (MIM 600521) and COLEC11 (MIM 612502), which both encode proteins playing important roles in the lectin complement pathway, were found to be responsible for 3MC syndrome [3, 4]. While there is no recognized phenotypic difference, OMIM classifies individuals having mutations in MASP1 and COLEC11 under 3MC1 (MIM 257920) and 3MC2 (MIM 265050) syndromes, respectively. The MASP1 gene is located on chromosome 3q27-28 and gives rise to three alternative splice products playing roles in the lectin pathway of the innate immune system: MASP-1, MASP-3, and MAp44 [5–7]. The gene is composed of 18 exons; the three alternative splice products share the same first eight exons encoding the first four domains of the proteins. The serine protease (SP) domains of MASP-1 and MASP-3 are encoded by separate exons, whereas no SP domain is present in MAp44 (Fig. 1). The SP domain of MASP-1 is encoded by six separate exons (13–18), while MASP-3 is encoded by a single exon (12) [8–10]. In this study, we report on six previously unreported children with 3MC1 syndrome and the results of their molecular investigations.Fig. 1


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

Atik T, Koparir A, Bademci G, Foster J, Altunoglu U, Mutlu GY, Bowdin S, Elcioglu N, Tayfun GA, Atik SS, Ozen M, Ozkinay F, Alanay Y, Kayserili H, Thiel S, Tekin M - Orphanet J Rare Dis (2015)

a Overview of MASP1 mutations. Exons and introns are indicated by circles with numbers and thin lines, respectively. The localization of mutations identified in this study is shown with blue arrows; those reported by Sirmaci et al.[3] and Rooryck et al. [4] are shown with red arrows; b Overview of the resulting protein structures of the three mRNA sequences produced from MASP1. In protein domains of these different transcripts, the blue arrows and red arrows show the mutations presented in this study and reported previously, respectively [3, 4]
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4589207&req=5

Fig1: a Overview of MASP1 mutations. Exons and introns are indicated by circles with numbers and thin lines, respectively. The localization of mutations identified in this study is shown with blue arrows; those reported by Sirmaci et al.[3] and Rooryck et al. [4] are shown with red arrows; b Overview of the resulting protein structures of the three mRNA sequences produced from MASP1. In protein domains of these different transcripts, the blue arrows and red arrows show the mutations presented in this study and reported previously, respectively [3, 4]
Mentions: Mutations in two genes, MASP1 (MIM 600521) and COLEC11 (MIM 612502), which both encode proteins playing important roles in the lectin complement pathway, were found to be responsible for 3MC syndrome [3, 4]. While there is no recognized phenotypic difference, OMIM classifies individuals having mutations in MASP1 and COLEC11 under 3MC1 (MIM 257920) and 3MC2 (MIM 265050) syndromes, respectively. The MASP1 gene is located on chromosome 3q27-28 and gives rise to three alternative splice products playing roles in the lectin pathway of the innate immune system: MASP-1, MASP-3, and MAp44 [5–7]. The gene is composed of 18 exons; the three alternative splice products share the same first eight exons encoding the first four domains of the proteins. The serine protease (SP) domains of MASP-1 and MASP-3 are encoded by separate exons, whereas no SP domain is present in MAp44 (Fig. 1). The SP domain of MASP-1 is encoded by six separate exons (13–18), while MASP-3 is encoded by a single exon (12) [8–10]. In this study, we report on six previously unreported children with 3MC1 syndrome and the results of their molecular investigations.Fig. 1

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

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.

No MeSH data available.


Related in: MedlinePlus