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Ornithine carbamoyltransferase deficiency: molecular characterization of 29 families
Author(s) -
Storkanova G,
Vlaskova H,
Chuzhanova N,
Zeman J,
Stranecky V,
Majer F,
Peskova K,
Luksan O,
Jirsa M,
Hrebicek M,
Dvorakova L
Publication year - 2013
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.12085
Subject(s) - ornithine carbamoyltransferase , missense mutation , genetics , urea cycle , biology , mutation , exon , compound heterozygosity , microbiology and biotechnology , heterozygote advantage , enzyme , ornithine , gene , biochemistry , genotype , amino acid , arginine
Ornithine carbamoyltransferase deficiency is the most common inherited defect of the urea cycle. We examined 28 male and 9 female patients from 29 families and identified 25 distinct mutations in OTC , 14 of which were novel. Three novel missense mutations (p. Ala102Pro , p. Pro158Ser , p. Lys210Glu ) and a novel deletion of the Leu43 are not directly involved either in the enzyme active site or in the intersubunit interactions; however, the mutations include conserved residues involved in intramolecular interaction network essential for the function of the enzyme. Three novel large deletions – a 444 kb deletion affecting RPGR , OTC and TSPAN7 , a 10 kb‐deletion encompassing OTC exons 5 and 6 and a 24.5 kb‐deletion encompassing OTC exons 9 and 10 – have probably been initiated by double strand breaks at recombination‐promoting motifs with subsequent non‐homologous end joining repair. Finally, we present a manifesting heterozygote carrying a hypomorphic mutation p. Arg129His in combination with unfavorably skewed X‐inactivation in three peripheral tissues.