title: WDR73 missense mutation causes infantile onset intellectual disability and cerebellar hypoplasia in a consanguineous family.
abstract: Galloway-Mowat syndrome (GMS) is a very rare autosomal-recessive disorder characterized by nephrotic syndrome associated with microcephaly, and various central nervous system abnormalities, mostly cerebral hypoplasia or cerebellar atrophy, intellectual disability and neural-migration defects. WDR73 is the only gene known to cause GMS, and has never been implicated in other disease. Here we present a Chinese consanguineous family with infantile onset intellectual disability and cerebellar hypoplasia but no microcephaly. Whole exome sequencing identified a WDR73 p.W371G missense mutation. The mutation is confirmed to be segregated in this family by Sanger sequencing according to a recessive inheritance pattern. It is predicted to be deleterious by multiple algorithms and affect highly conserved site. Structural modeling revealed conformational differences between the wild type protein and the p.W371G protein. Real-time PCR and Western blotting revealed altered mRNA and protein levels in mutated samples. Our study indicates the novel WDR73 p.W371G missense mutation causes infantile onset intellectual disability and cerebellar hypoplasia in recessive mode of inheritance. Our findings imply that microcephaly is a variable phenotype in WDR73-related disease, suggest WDR73 to be a candidate gene of severe intellectual disability and cerebellar hypoplasia, and expand the molecular spectrum of WDR73-related disease.
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, 110 Xiangya Road, Changsha, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, 110 Xiangya Road, Changsha, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Gai
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, 110 Xiangya Road, Changsha, China.
authors.forename: Yongyi
authors.initials: Y
authors.lastname: Zou
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, 110 Xiangya Road, Changsha, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, 110 Xiangya Road, Changsha, China.
authors.forename: Ruiyu
authors.initials: R
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, 110 Xiangya Road, Changsha, China.
authors.forename: Xianda
authors.initials: X
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, 110 Xiangya Road, Changsha, China.
authors.forename: Desheng
authors.initials: D
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, 110 Xiangya Road, Changsha, China. Electronic address: wulingqian@sklmg.edu.cn.
authors.forename: Lingqian
authors.initials: L
authors.lastname: Wu
mesh_terms: D000328:Adult; D017668:Age of Onset; D000595:Amino Acid Sequence; D000818:Animals; D002531:Cerebellum / Q000002:abnormalities*; D003241:Consanguinity; D002658:Developmental Disabilities / Q000150:complications / Q000209:etiology / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000150:complications / Q000209:etiology / Q000235:genetics*; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D009421:Nervous System Malformations / Q000150:complications / Q000209:etiology / Q000235:genetics*; D010375:Pedigree; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry / Q000235:genetics*
chemical_list: D011506:Proteins; C000595586:WDR73 protein, human
keywords: Cerebellar hypoplasia; Galloway-Mowat syndrome; Intellectual disability; WDR73