Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations

Axial spondylometaphyseal dysplasia (axial SMD) is an autosomal recessive disease characterized by dysplasia of axial skeleton and retinal dystrophy. We conducted whole exome sequencing and identified C21orf2 (chromosome 21 open reading frame 2) as a disease gene for axial SMD. C21orf2 mutations hav...

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Published in:PloS one 2016-03, Vol.11 (3), p.e0150555-e0150555
Main Authors: Wang, Zheng, Iida, Aritoshi, Miyake, Noriko, Nishiguchi, Koji M, Fujita, Kosuke, Nakazawa, Toru, Alswaid, Abdulrahman, Albalwi, Mohammed A, Kim, Ok-Hwa, Cho, Tae-Joon, Lim, Gye-Yeon, Isidor, Bertrand, David, Albert, Rustad, Cecilie F, Merckoll, Else, Westvik, Jostein, Stattin, Eva-Lena, Grigelioniene, Giedre, Kou, Ikuyo, Nakajima, Masahiro, Ohashi, Hirohumi, Smithson, Sarah, Matsumoto, Naomichi, Nishimura, Gen, Ikegawa, Shiro
Format: Article
Language:English
Subjects:
Acids
Adolescent
Analysis
Axial skeleton
Bioinformatics
Biology and Life Sciences
Bones
Cartilage
Cartilage - metabolism
Cartilage - pathology
Causes of
Cell Differentiation - genetics
Child
Child, Preschool
Children & youth
Chondrocytes
Chondrogenesis
Chromosome 21
Connecting rods
Degeneration
Disease control
Dysplasia
Dystrophy
Female
Gene expression
Gene Expression Regulation
Gene mutation
Genetic aspects
Genetic Diseases, Inborn - diagnostic imaging
Genetic Diseases, Inborn - genetics
Genetic Diseases, Inborn - metabolism
Genetics
Hospitals
Humans
Jeune syndrome
Laboratories
Male
Medicin och hälsovetenskap
Medicine
Medicine and Health Sciences
Military reserves
Mutation
Osteochondrodysplasias - diagnostic imaging
Osteochondrodysplasias - genetics
Osteochondrodysplasias - metabolism
Patients
Phenotype
Photoreceptors
Physiological aspects
Proteins
Proteins - genetics
Proteins - metabolism
Publishing
Radiography
Radiology
Research and analysis methods
Retina
Retina - metabolism
Retina - pathology
Retinal degeneration
Ribonucleic acid
RNA
Skeleton
Social Sciences
Splicing
Spondylometaphyseal dysplasia
University graduates
Young Adult
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Summary:Axial spondylometaphyseal dysplasia (axial SMD) is an autosomal recessive disease characterized by dysplasia of axial skeleton and retinal dystrophy. We conducted whole exome sequencing and identified C21orf2 (chromosome 21 open reading frame 2) as a disease gene for axial SMD. C21orf2 mutations have been recently found to cause isolated retinal degeneration and Jeune syndrome. We found a total of five biallelic C21orf2 mutations in six families out of nine: three missense and two splicing mutations in patients with various ethnic backgrounds. The pathogenic effects of the splicing (splice-site and branch-point) mutations were confirmed on RNA level, which showed complex patterns of abnormal splicing. C21orf2 mutations presented with a wide range of skeletal phenotypes, including cupped and flared anterior ends of ribs, lacy ilia and metaphyseal dysplasia of proximal femora. Analysis of patients without C21orf2 mutation indicated genetic heterogeneity of axial SMD. Functional data in chondrocyte suggest C21orf2 is implicated in cartilage differentiation. C21orf2 protein was localized to the connecting cilium of the cone and rod photoreceptors, confirming its significance in retinal function. Our study indicates that axial SMD is a member of a unique group of ciliopathy affecting skeleton and retina.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0150555