Novel findings in patients with primary hyperoxaluria type III and implications for advanced molecular testing strategies

TY - JOUR

T1 - Novel findings in patients with primary hyperoxaluria type III and implications for advanced molecular testing strategies

AU - Beck, Bodo B

AU - Baasner, Anne

AU - Buescher, Anja

AU - Habbig, Sandra

AU - Reintjes, Nadine

AU - Kemper, Markus J

AU - Sikora, Przemyslaw

AU - Mache, Christoph

AU - Pohl, Martin

AU - Stahl, Mirjam

AU - Toenshoff, Burkhard

AU - Pape, Lars

AU - Fehrenbach, Henry

AU - Jacob, Dorrit E

AU - Grohe, Bernd

AU - Wolf, Matthias T

AU - Nürnberg, Gudrun

AU - Yigit, Gökhan

AU - Salido, Eduardo C

AU - Hoppe, Bernd

PY - 2013/2/1

Y1 - 2013/2/1

N2 - Identification of mutations in the HOGA1 gene as the cause of autosomal recessive primary hyperoxaluria (PH) type III has revitalized research in the field of PH and related stone disease. In contrast to the well-characterized entities of PH type I and type II, the pathophysiology and prevalence of type III is largely unknown. In this study, we analyzed a large cohort of subjects previously tested negative for type I/II by complete HOGA1 sequencing. Seven distinct mutations, among them four novel, were found in 15 patients. In patients of non-consanguineous European descent the previously reported c.700+5G>T splice-site mutation was predominant and represents a potential founder mutation, while in consanguineous families private homozygous mutations were identified throughout the gene. Furthermore, we identified a family where a homozygous mutation in HOGA1 (p.P190L) segregated in two siblings with an additional AGXT mutation (p.D201E). The two girls exhibiting triallelic inheritance presented a more severe phenotype than their only mildly affected p.P190L homozygous father. In silico analysis of five mutations reveals that HOGA1 deficiency is causing type III, yet reduced HOGA1 expression or aberrant subcellular protein targeting is unlikely to be the responsible pathomechanism. Our results strongly suggest HOGA1 as a major cause of PH, indicate a greater genetic heterogeneity of hyperoxaluria, and point to a favorable outcome of type III in the context of PH despite incomplete or absent biochemical remission. Multiallelic inheritance could have implications for genetic testing strategies and might represent an unrecognized mechanism for phenotype variability in PH.

AB - Identification of mutations in the HOGA1 gene as the cause of autosomal recessive primary hyperoxaluria (PH) type III has revitalized research in the field of PH and related stone disease. In contrast to the well-characterized entities of PH type I and type II, the pathophysiology and prevalence of type III is largely unknown. In this study, we analyzed a large cohort of subjects previously tested negative for type I/II by complete HOGA1 sequencing. Seven distinct mutations, among them four novel, were found in 15 patients. In patients of non-consanguineous European descent the previously reported c.700+5G>T splice-site mutation was predominant and represents a potential founder mutation, while in consanguineous families private homozygous mutations were identified throughout the gene. Furthermore, we identified a family where a homozygous mutation in HOGA1 (p.P190L) segregated in two siblings with an additional AGXT mutation (p.D201E). The two girls exhibiting triallelic inheritance presented a more severe phenotype than their only mildly affected p.P190L homozygous father. In silico analysis of five mutations reveals that HOGA1 deficiency is causing type III, yet reduced HOGA1 expression or aberrant subcellular protein targeting is unlikely to be the responsible pathomechanism. Our results strongly suggest HOGA1 as a major cause of PH, indicate a greater genetic heterogeneity of hyperoxaluria, and point to a favorable outcome of type III in the context of PH despite incomplete or absent biochemical remission. Multiallelic inheritance could have implications for genetic testing strategies and might represent an unrecognized mechanism for phenotype variability in PH.

KW - Adolescent

KW - Adult

KW - Cell Culture Techniques

KW - Female

KW - Gene Expression

KW - Genetic Testing

KW - Humans

KW - Hyperoxaluria, Primary

KW - Kidney Calculi

KW - Male

KW - Middle Aged

KW - Mutation

KW - Oxo-Acid-Lyases

KW - Pedigree

U2 - 10.1038/ejhg.2012.139

DO - 10.1038/ejhg.2012.139

M3 - SCORING: Journal article

C2 - 22781098

VL - 21

SP - 162

EP - 172

JO - EUR J HUM GENET

JF - EUR J HUM GENET

SN - 1018-4813

IS - 2

ER -