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Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria.
Hopp, Katharina; Cogal, Andrea G; Bergstralh, Eric J; Seide, Barbara M; Olson, Julie B; Meek, Alicia M; Lieske, John C; Milliner, Dawn S; Harris, Peter C.
Afiliação
  • Hopp K; Division of Nephrology and Hypertension.
  • Cogal AG; Division of Nephrology and Hypertension.
  • Bergstralh EJ; Division of Biomedical Statistics and Informatics.
  • Seide BM; Division of Nephrology and Hypertension.
  • Olson JB; Division of Nephrology and Hypertension.
  • Meek AM; Division of Nephrology and Hypertension.
  • Lieske JC; Division of Nephrology and Hypertension.
  • Milliner DS; Division of Nephrology and Hypertension, Division of Pediatric Nephrology, Mayo Clinic, Rochester, Minnesota.
  • Harris PC; Division of Nephrology and Hypertension, Department of Biochemistry and Molecular Biology, and harris.peter@mayo.edu.
J Am Soc Nephrol ; 26(10): 2559-70, 2015 Oct.
Article em En | MEDLINE | ID: mdl-25644115
Primary hyperoxaluria (PH) is a rare autosomal recessive disease characterized by oxalate accumulation in the kidneys and other organs. Three loci have been identified: AGXT (PH1), GRHPR (PH2), and HOGA1 (PH3). Here, we compared genotype to phenotype in 355 patients in the Rare Kidney Stone Consortium PH registry and calculated prevalence using publicly available whole-exome data. PH1 (68.4% of families) was the most severe PH type, whereas PH3 (11.0% of families) showed the slowest decline in renal function but the earliest symptoms. A group of patients with disease progression similar to that of PH3, but for whom no mutation was detected (11.3% of families), suggested further genetic heterogeneity. We confirmed that the AGXT p.G170R mistargeting allele resulted in a milder PH1 phenotype; however, other potential AGXT mistargeting alleles caused more severe (fully penetrant) disease. We identified the first PH3 patient with ESRD; a homozygote for two linked, novel missense mutations. Population analysis suggested that PH is an order of magnitude more common than determined from clinical cohorts (prevalence, approximately 1:58,000; carrier frequency, approximately 1:70). We estimated PH to be approximately three times less prevalent among African Americans than among European Americans because of a limited number of common European origin alleles. PH3 was predicted to be as prevalent as PH1 and twice as common as PH2, indicating that PH3 (and PH2) cases are underdiagnosed and/or incompletely penetrant. These results highlight a role for molecular analyses in PH diagnostics and prognostics and suggest that wider analysis of the idiopathic stone-forming population may be beneficial.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Hiperoxalúria Primária / Estudos de Associação Genética / Heterozigoto Tipo de estudo: Risk_factors_studies Limite: Adolescent / Adult / Aged / Child / Child, preschool / Humans / Infant / Middle aged Idioma: En Ano de publicação: 2015 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Hiperoxalúria Primária / Estudos de Associação Genética / Heterozigoto Tipo de estudo: Risk_factors_studies Limite: Adolescent / Adult / Aged / Child / Child, preschool / Humans / Infant / Middle aged Idioma: En Ano de publicação: 2015 Tipo de documento: Article