title: Splice, insertion-deletion and nonsense mutations that perturb the phenylalanine hydroxylase transcript cause phenylketonuria in India.
abstract: Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by mutational inactivation of the phenylalanine hydroxylase (PAH) gene. Missense mutations are the most common PAH mutation type detected in PKU patients worldwide. We performed PAH mutation analysis in 27 suspected Indian PKU families (including 7 from our previous study) followed by structure and function analysis of specific missense and splice/insertion-deletion/nonsense mutations, respectively. Of the 27 families, disease-causing mutations were detected in 25. A total of 20 different mutations were identified of which 7 "unique" mutations accounted for 13 of 25 mutation positive families. The unique mutations detected exclusively in Indian PKU patients included three recurrent mutations detected in three families each. The 20 mutations included only 5 missense mutations in addition to 5 splice, 4 each nonsense and insertion-deletion mutations, a silent variant in coding region and a 3'UTR mutation. One deletion and two nonsense mutations were characterized to confirm significant reduction in mutant transcript levels possibly through activation of nonsense mediated decay. All missense mutations affected conserved amino acid residues and sequence and structure analysis suggested significant perturbations in the enzyme activity of respective mutant proteins. This is probably the first report of identification of a significantly low proportion of missense PAH mutations from PKU families and together with the presence of a high proportion of splice, insertion-deletion, and nonsense mutations, points to a unique PAH mutation profile in Indian PKU patients.
authors.affiliation: Laboratory of Molecular Oncology, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India.
authors.forename: Murali D
authors.initials: MD
authors.lastname: Bashyam
authors.forename: Ajay K
authors.initials: AK
authors.lastname: Chaudhary
authors.forename: Manjari
authors.initials: M
authors.lastname: Kiran
authors.forename: Hampapathalu A
authors.initials: HA
authors.lastname: Nagarajaram
authors.forename: Radha Rama
authors.initials: RR
authors.lastname: Devi
authors.forename: Prajnya
authors.initials: P
authors.lastname: Ranganath
authors.forename: Ashwin
authors.initials: A
authors.lastname: Dalal
authors.forename: Leena
authors.initials: L
authors.lastname: Bashyam
authors.forename: Neerja
authors.initials: N
authors.lastname: Gupta
authors.forename: Madhulika
authors.initials: M
authors.lastname: Kabra
authors.forename: Mamta
authors.initials: M
authors.lastname: Muranjan
authors.forename: Ratna D
authors.initials: RD
authors.lastname: Puri
authors.forename: Ishwar C
authors.initials: IC
authors.lastname: Verma
authors.forename: Sheela
authors.initials: S
authors.lastname: Nampoothiri
authors.forename: Jayarama S
authors.initials: JS
authors.lastname: Kadandale
mesh_terms: D000483:Alleles; D044466:Asian People / Q000235:genetics; D018389:Codon, Nonsense / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics*; D007194:India; D008297:Male; D010375:Pedigree; D010651:Phenylalanine Hydroxylase / Q000235:genetics* / Q000378:metabolism; D010661:Phenylketonurias / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D022821:RNA Splice Sites / Q000235:genetics
chemical_list: D018389:Codon, Nonsense; D022821:RNA Splice Sites; D010651:Phenylalanine Hydroxylase
keywords: NONSENSE MEDIATED DECAY; PAH TRANSCRIPT; PHENYLALANINE HYDROXYLASE; PHENYLKETONURIA; SPLICE SITE MUTATION