title: Spectrum of CREBBP mutations in Indian patients with Rubinstein-Taybi syndrome.
abstract: Rubinstein-Taybi syndrome (RSTS), a developmental disorder comprising abnormalities that include mental retardation, an unusual facial appearance, broad thumbs and big toes is frequently associated with molecular lesions in the CREB-binding protein gene, CREBBP. The objective of the present study was to identify and analyse CREBBP mutations in Indian RSTS patients on which there are no data. Direct sequencing of CREBBP performed in 13 RSTS patients identified the three zinc fingers (CH1, CH2, CH3) and HAT domain as mutational hotspots in which ten novel pathogenic mutations were localized. Functional analysis revealed that three of these mutations affecting amino acids Glu1459, Leu1668 and Glu1724 were critical for histone acetyltransferase activity. Twenty-eight novel CREBBP single-nucleotide polymorphisms (SNPs) were also identified in the Indian population. Linkage disequilibrium studies revealed associations between (i) SNP (rs129974/c.3836-206G greater than C) and mutation (p.Asp1340Ala); (ii) (rs130002) with mutation (p.Asn435Lys) and (iii) SNPs rs129974, rs130002 and SNP (c.3836-206G greater than C) signifying a disease affection status. In conclusion, the present study reports the highest detection rate of CREBBP mutations (76.9%) in RSTS patients to date, of which ten are predicted to be pathogenic and three critical for histone acetyltransferase activity. Moreover, identification of the association of CREBBP polymorphisms with disease susceptibility could be an important risk factor for the pathogenesis of RSTS.
authors.affiliation: National Centre for Cell Science, NCCS Complex, Pune University Complex, Ganeshkhind, Pune 411 007, India.
authors.forename: Neeti
authors.initials: N
authors.lastname: Sharma
authors.forename: Avinash M
authors.initials: AM
authors.lastname: Mali
authors.forename: Sharmila A
authors.initials: SA
authors.lastname: Bapat
mesh_terms: D050882:CREB-Binding Protein / Q000737:chemistry / Q000145:classification / Q000235:genetics*; D004252:DNA Mutational Analysis; D005819:Genetic Markers; D006801:Humans; D007194:India; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D012415:Rubinstein-Taybi Syndrome / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology
chemical_list: D005819:Genetic Markers; D050882:CREB-Binding Protein; C494363:CREBBP protein, human