Phenylketonuria mutant alleles in different populations: missense mutation in exon 7 of phenylalanine hydroxylase gene

Takarada, Yutaka; Kalanin, J; Yamashita, Keiko; Ohtsuka, N; Kagawa, Shingo; Matsuoka, Atsuko

doi:10.1093/clinchem/39.11.2354

Cited by 10 publications

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“…The p.Y206X mutation was reported earlier from China [Song et al, ] and from other populations [Erlandsen and Stevens, ]. The p.R158W mutation is also reported from China [Takarada et al, ] and Korea [Takarada et al, ]; similarly the p.R252Q has been reported from Taiwan [Chien et al, ]. The p.P281L mutation is reported to be a common mutation in the Mediterranean population [Perez et al, ] and has been suggested to induce skipping of exon 8, though the mutation itself is located in exon 7.…”

Section: Discussionmentioning

confidence: 94%

Splice, Insertion‐Deletion and Nonsense Mutations that Perturb the Phenylalanine Hydroxylase Transcript Cause Phenylketonuria in India

Bashyam

Chaudhary

Kiran

et al. 2014

J of Cellular Biochemistry

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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.

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