title: Mutations and novel polymorphisms in coding regions and UTRs of CDK5R1 and OMG genes in patients with non-syndromic mental retardation.
abstract: Mental retardation (MR) is displayed by 57% of NF1 patients with microdeletion syndrome as a result of 17q11.2 region haploinsufficiency. We considered the cyclin-dependent kinase 5 regulatory subunit 1 (CDK5R1) and oligodendrocyte-myelin glycoprotein (OMG) genes, mapping in the NF1 microdeleted region, as candidate genes for MR susceptibility. CDK5R1 encodes for a neurone-specific activator of cyclin-dependent kinase 5 (CDK5) involved in neuronal migration during central nervous system development. OMG encodes for an inhibitor of neurite outgrowth by the binding to the Nogo-66 receptor (RTN4R). CDK5R1 and OMG genes are characterized by large 3' and 5' untranslated regions (UTRs), where we predict the presence of several transcription/translation regulatory elements. We screened 100 unrelated Italian patients affected by unspecific MR for mutations in CDK5R1 and OMG coding regions and in their 3' or 5' UTRs. Four novel mutations and two novel polymorphisms for CDK5R1 and three novel mutations for OMG were detected, including two missense changes (c.323C>T; A108V in CDK5R1 and c.1222A>G; T408A in OMG), one synonymous codon variant (c.532C>T; L178L in CDK5R1), four variants in CDK5R1 3'UTR and two changes in OMG 5'UTR. All the mutations were absent in 370 chromosomes from normal subjects. The allelic frequencies of the two novel polymorphisms in CDK5R1 3'UTR were established in both 185 normal and 100 mentally retarded subjects. Prediction of mRNA and protein secondary structures revealed that two changes lead to putative structural alterations in the mutated c.2254C>G CDK5R1 3'UTR and in OMG T408A gene product.
authors.affiliation: Department of Biology and Genetics, Medical Faculty, University of Milan, Via Viotti 3/5, 20133, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Venturin
authors.forename: Silvia
authors.initials: S
authors.lastname: Moncini
authors.forename: Valentina
authors.initials: V
authors.lastname: Villa
authors.forename: Silvia
authors.initials: S
authors.lastname: Russo
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Bonati
authors.forename: Lidia
authors.initials: L
authors.lastname: Larizza
authors.forename: Paola
authors.initials: P
authors.lastname: Riva
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D058851:GPI-Linked Proteins; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000235:genetics*; D063308:Myelin-Oligodendrocyte Glycoprotein; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009690:Nucleic Acid Conformation; D011110:Polymorphism, Genetic; D016415:Sequence Alignment; D020506:Untranslated Regions / Q000235:genetics*
chemical_list: D058851:GPI-Linked Proteins; C571326:MOG protein, human; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D009419:Nerve Tissue Proteins; C560528:OMG protein, human; D020506:Untranslated Regions; C089495:neuronal Cdk5 activator (p25-p35)