Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies

Sci Rep. 2017 Nov 14;7(1):15585. doi: 10.1038/s41598-017-15442-1.

A Hammarsjö ¹ ², Z Wang ³ ⁴, R Vaz ¹, F Taylan ¹, M Sedghi ⁵, K M Girisha ⁶, D Chitayat ⁷ ⁸, K Neethukrishna ⁶, P Shannon ⁹, R Godoy ⁷, K Gowrishankar ¹⁰, A Lindstrand ¹ ², J Nasiri ¹¹, M Baktashian ¹², P T Newton ¹³, L Guo ³, W Hofmeister ¹, M Pettersson ¹ ², A S Chagin ¹³, G Nishimura ¹⁴, L Yan ¹⁵, N Matsumoto ¹⁶, A Nordgren ¹ ², N Miyake ¹⁶, G Grigelioniene ¹⁷ ¹⁸, S Ikegawa ¹⁹

Affiliations

1 Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
2 Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
3 Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
4 Department of Medical Genetics, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
5 Medical Genetics Laboratory, Alzahra University Hospital, Isfahan University of Medical Sciences, Isfahan, Iran.
6 Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, India.
7 The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
8 Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
9 Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
10 Medical Genetics, Kanchi Kamakoti Childs Trust Hospital, Chennai, Tamilnadu, India.
11 Department of Pediatric Neurology, Faculty of Medicine, Child Growth and Development Research Center, Isfahan University of Medical sciences, Isfahan, Iran.
12 Student Research Committee, Department of Modern Sciences and Technologies, Faculty of medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
13 Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
14 Intractable Disease Center, Saitama University Hospital, Saitama, Japan.
15 Department of Neurology, China-Japan Friendship Hospital, Beijing, China.
16 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
17 Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. [email protected].
18 Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden. [email protected].
19 Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan. [email protected].

PMID: 29138412 DOI: 10.1038/s41598-017-15442-1

Abstract

The skeletal ciliopathies are a heterogeneous group of disorders with a significant clinical and genetic variability and the main clinical features are thoracic hypoplasia and short tubular bones. To date, 25 genes have been identified in association with skeletal ciliopathies. Mutations in the KIAA0753 gene have recently been associated with Joubert syndrome (JBTS) and orofaciodigital (OFD) syndrome. We report biallelic pathogenic variants in KIAA0753 in four patients with short-rib type skeletal dysplasia. The manifestations in our patients are variable and ranging from fetal lethal to viable and moderate skeletal dysplasia with narrow thorax and abnormal metaphyses. We demonstrate that KIAA0753 is expressed in normal fetal human growth plate and show that the affected fetus, with a compound heterozygous frameshift and a nonsense mutation in KIAA0753, has an abnormal proliferative zone and a broad hypertrophic zone. The importance of KIAA0753 for normal skeletal development is further confirmed by our findings that zebrafish embryos homozygous for a nonsense mutation in kiaa0753 display altered cartilage patterning.

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