title: Targeted deep resequencing identifies MID2 mutation for X-linked intellectual disability with varied disease severity in a large kindred from India.
abstract: We report a novel missense mutation (c.1040G>A, p.Arg347Gln) in MID2, which encodes ubiquitin ligase E3, as the likely cause of X-linked mental retardation in a large kindred. The mutation was observed in all affected and obligate carriers but not in any unaffected males of the family or in population controls (n = 200). When transiently expressed in HEK293T cell line, the mutation was found to abolish the function of the COS domain in the protein. The GFP-tagged mutant protein accumulated in the cytoplasm instead of binding to the cytoskeleton resulting in its altered subcellular localization. Screening of coding exons of this gene in additional 480 unrelated individuals with idiopathic intellectual disability identified another novel variation p.Asn343Ser. This study highlights the growing role of the ubiquitin pathway in intellectual disability and also, the difference in MID2 determined phenotype observed in this study compared with that of its paralogue MID1 reported in literature.
authors.affiliation: Department of Genetics, University of Delhi South Campus, New Delhi, India.
authors.forename: Thenral S
authors.initials: TS
authors.lastname: Geetha
authors.forename: Kulandaimanuvel Antony
authors.initials: KA
authors.lastname: Michealraj
authors.forename: Madhulika
authors.initials: M
authors.lastname: Kabra
authors.forename: Gurjit
authors.initials: G
authors.lastname: Kaur
authors.forename: Ramesh C
authors.initials: RC
authors.lastname: Juyal
authors.forename: B K
authors.initials: BK
authors.lastname: Thelma
mesh_terms: D001665:Binding Sites; D041321:Chromosomes, Human, X / Q000235:genetics; D003593:Cytoplasm / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D005091:Exons; D005260:Female; D014644:Genetic Variation; D057809:HEK293 Cells; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007194:India; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics*; D008868:Microtubule Proteins / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism*; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
chemical_list: C121118:MID2 protein, human; D008868:Microtubule Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C109052:MID1 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: MID2; X-linked intellectual disability; linkage analysis; targeted resequencing