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Calcif Tissue Int. 2017 Jan;100(1):55-66. doi: 10.1007/s00223-016-0201-z. Epub 2016 Oct 28.

Novel Mutations in SERPINF1 Result in Rare Osteogenesis Imperfecta Type VI.

Author information

1
Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Shuaifuyuan No. 1, Dongcheng District, Beijing, 100730, China.
2
Department of Cardiology, FuWai Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, 100037, China.
3
Binhai Genomics Institute, BGI-Tianjin, BGI-shenzhen, Tianjin, 300308, China.
4
Tianjin Translational Genomics Center, BGI-Tianjin, BGI-shenzhen, Tianjin, 300308, China.
5
BGI-shenzhen, Shenzhen, 518083, China.
6
James D. Watson Institute of Genome Sciences, Hangzhou, 310058, China.
7
Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Shuaifuyuan No. 1, Dongcheng District, Beijing, 100730, China. limeilzh@sina.com.

Abstract

Osteogenesis imperfecta (OI) is a group of inherited disorders characterized by recurrent fragile fractures. Serpin peptidase inhibitor, clade F, member 1 (SERPINF1) is known to cause a distinct, extremely rare autosomal recessive form of type VI OI. Here we report, for the first time, the detection of SERPINF1 mutations in Chinese OI patients. We designed a novel targeted next-generation sequencing panel of OI-related genes to identify pathogenic mutations, which were confirmed with Sanger sequencing and by co-segregation analysis. We also investigated the phenotypes of OI patients by evaluating bone mineral density, radiological fractures, serum bone turnover markers, and pigment epithelium-derived factor (PEDF) concentration. Six patients with moderate-to-severe bone fragility, significantly low bone mineral density, and severe deformities of the extremities were recruited from five unrelated families for this study. Six pathogenic mutations in SERPINF1 gene were identified, five of which were novel: (1) a homozygous in-frame insertion in exon 3 (c.271_279dup, p.Ala91_Ser93dup); (2) compound heterozygous mutations in intron 3 (c.283 + 1G > T, splicing site) and exon 5 (c.498_499delCA, p.Arg167SerfsX35, frameshift); (3) a homozygous frameshift mutation in exon 8 (c.1202_1203delCA, p.Thr401ArgfsX); (4) compound heterozygous missense mutation (c.184G > A, p.Gly62Ser) and in-frame insertion (c.271_279dup, p.Ala91_Ser93dup) in exon 3; and (5) a heterozygous nonsense mutation in exon 4 (c.397C>T + ?, p.Gln133X + ?). Serum PEDF levels were barely detectable in almost all subjects. We identified five novel mutations in SERPINF1 and confirmed the diagnostic value of serum PEDF level for the first time in Chinese patients with the extremely rare OI type VI.

KEYWORDS:

Osteogenesis imperfecta; PEDF; SERPINF1 mutation; Type VI OI

PMID:
27796462
DOI:
10.1007/s00223-016-0201-z
[Indexed for MEDLINE]

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