title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
abstract: 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.
authors.affiliation: Laboratory of Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, 108-8639, Japan.|McKusick-Zhang Center for Genetic Medicine and State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100005, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Laboratory of Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, 108-8639, Japan.
authors.forename: Aritoshi
authors.initials: A
authors.lastname: Iida
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.affiliation: Department of Advanced Ophthalmic Medicine, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.
authors.forename: Koji M
authors.initials: KM
authors.lastname: Nishiguchi
authors.affiliation: Department of Retinal Disease Control, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Fujita
authors.affiliation: Department of Advanced Ophthalmic Medicine, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.|Department of Retinal Disease Control, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.|Department of Opthalmology, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Nakazawa
authors.affiliation: Department of Pediatrics, King Abdulaziz Medical City for National Guard Health Affairs, Riyadh, 22490, Saudi Arabia.
authors.forename: Abdulrahman
authors.initials: A
authors.lastname: Alswaid
authors.affiliation: Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City, National Guard Health Affairs, Riyadh, 22490, Saudi Arabia.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Albalwi
authors.affiliation: Department of Radiology, Woorisoa Children's Hospital, Seoul, 08291, Republic of Korea.
authors.forename: Ok-Hwa
authors.initials: OH
authors.lastname: Kim
authors.affiliation: Department of Orthopaedic Surgery, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
authors.forename: Tae-Joon
authors.initials: TJ
authors.lastname: Cho
authors.affiliation: Department of Radiology, St. Mary's Hospital, The Catholic University, Seoul, 07345, Republic of Korea.
authors.forename: Gye-Yeon
authors.initials: GY
authors.lastname: Lim
authors.affiliation: CHU Nantes, Service de Génétique Médicale and INSERM, UMR-S 957, Nantes, 44093, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Isidor
authors.affiliation: CHU Nantes, Service de Génétique Médicale and INSERM, UMR-S 957, Nantes, 44093, France.
authors.forename: Albert
authors.initials: A
authors.lastname: David
authors.affiliation: Department of Medical Genetics, Section for Clinical Genetics, Oslo University Hospital, Oslo, 0424, Norway.
authors.forename: Cecilie F
authors.initials: CF
authors.lastname: Rustad
authors.affiliation: Department of Radiology, Oslo University Hospital, Oslo, 0424, Norway.
authors.forename: Else
authors.initials: E
authors.lastname: Merckoll
authors.affiliation: Department of Radiology, Oslo University Hospital, Oslo, 0424, Norway.
authors.forename: Jostein
authors.initials: J
authors.lastname: Westvik
authors.affiliation: Department of Medical Biosciences, Medical and Clinical Genetics, Umeå University, Umeå, 90187, Sweden.
authors.forename: Eva-Lena
authors.initials: EL
authors.lastname: Stattin
authors.affiliation: Department of Clinical Genetics and Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, 17176, Sweden.
authors.forename: Giedre
authors.initials: G
authors.lastname: Grigelioniene
authors.affiliation: Laboratory of Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, 108-8639, Japan.
authors.forename: Ikuyo
authors.initials: I
authors.lastname: Kou
authors.affiliation: Laboratory of Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, 108-8639, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakajima
authors.affiliation: Division of Medical Genetics, Saitama Children's Medical Center, Saitama, 339-8551, Japan.
authors.forename: Hirohumi
authors.initials: H
authors.lastname: Ohashi
authors.affiliation: Department of Clinical Genetics, St. Michaels Hospital, Bristol, BS2 8EG, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Smithson
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
authors.affiliation: Department of Pediatric Imaging, Tokyo Metropolitan Children's Medical Center, Fuchu, 183-8561, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Nishimura
authors.affiliation: Laboratory of Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, 108-8639, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
mesh_terms: D000293:Adolescent; D002356:Cartilage / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003598:Cytoskeletal Proteins; D005260:Female; D005786:Gene Expression Regulation; D030342:Genetic Diseases, Inborn / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D009154:Mutation; D010009:Osteochondrodysplasias / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D011859:Radiography; D012160:Retina / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: C111475:CFAP410 protein, human; D003598:Cytoskeletal Proteins; D011506:Proteins