Dataset Information

Amelioration of Sardinian beta0 thalassemia by genetic modifiers.

ABSTRACT: Sardinian beta-thalassemia patients all are homozygotes for the same null allele in the beta-globin gene, but the clinical manifestations are extremely variable in severity. Previous studies have shown that the coinheritance of alpha-thalassemia or the presence of genetic variants that sustain fetal hemoglobin production has a strong impact on ameliorating the clinical phenotype. Here we evaluate the contribution of variants in the BCL11A, and HBS1L-MYB genes, implicated in the regulation of fetal hemoglobin, and of alpha-thalassemia coinheritance in 50 thalassemia intermedia and 75 thalassemia major patients. We confirm that alpha-thalassemia and allele C of single nucleotide polymorphism rs-11886868 in BCL11A were selectively represented in thalassemia intermedia patients. Moreover, allele G at single nucleotide polymorphism rs9389268 in the HBS1L-MYB locus was significantly more frequent in the thalassemia intermedia patients. This trio of genetic factors can account for 75% of the variation differences in phenotype severity.

SUBMITTER: Galanello R

PROVIDER: S-EPMC2925722 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Amelioration of Sardinian beta0 thalassemia by genetic modifiers.

Galanello Renzo R Sanna Serena S Perseu Lucia L Sollaino Maria Carla MC Satta Stefania S Lai Maria Eliana ME Barella Susanna S Uda Manuela M Usala Gianluca G Abecasis Goncalo R GR Cao Antonio A

Blood 20090820 18

Sardinian beta-thalassemia patients all are homozygotes for the same null allele in the beta-globin gene, but the clinical manifestations are extremely variable in severity. Previous studies have shown that the coinheritance of alpha-thalassemia or the presence of genetic variants that sustain fetal hemoglobin production has a strong impact on ameliorating the clinical phenotype. Here we evaluate the contribution of variants in the BCL11A, and HBS1L-MYB genes, implicated in the regulation of fet ...[more]

PMID: 19696200

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Project description:Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD1 gene in both humans and the orthologous PCK rat model. Although ARPKD results solely from PKHD1 mutations, the disease onset and severity are highly variable, indicating that other unknown genetic risk factor(s) modify ARPKD-associated phenotypes. To identify genetic modifiers of ARPKD severity, we created two genetically distinct Pkhd1 congenic rat strains on the Fawn-Hooded Hypertensive (FHH) and the Dahl S (SS) rat backgrounds (denoted FHH.Pkhd1 and SS.Pkhd1, respectively) that harbor the PCK-derived Pkhd1 allele. The FHH.Pkhd1 and SS.Pkhd1 strains had lower renal cyst formation at 30 days-of-age (5±2% and 8±2% cystic, respectively; P<0.001) compared to the PCK kidneys (26±4% cystic), which coincided with significantly reduced kidney weights in the FHH.Pkhd1 and SS.Pkhd1. Liver cyst formation and liver weight did not differ between PCK, FHH.Pkhd1, and SS.Pkhd1. These data indicated that the PCK genome harbors genetic modifier(s) of ARPKD severity that are not present in the FHH and SS genomes. Using high density SNP array genotyping and microarray expression analysis, we identified 50 potential modifiers of ARPKD severity in the PCK rat. Of these candidates, a damaging nonsynonymous variant in Nphp4 stood out as the most likely candidate based on variant segregation, protein modeling, network analysis, and gene ontology. Nphp4 is widely associated with the autosomal recessive cilliopathy and nephronopthisis, but had not been previously implicated in the molecular or cellular pathophysiology of ARPKD. Collectively, these data provide genetic evidence of disease modifier(s) in the PCK model of ARPKD and prioritized multiple candidates, including NPHP4, for further investigation in ARPKD pathogenesis. In this study, we used microarray to analyze transcript expression in the kidneys of 30 day old SD (n=4), PCK (n=4), FHH (n=4), FHH.Pkhd1 (n=4), SS (n=4), and SS.Pkhd1 (n=4). Samples were pooled and the pooled samples were run in triplicate. The 30 day timepoint was chosen because the differences in renal cyst formation between PCK, FHH.Pkhd1, and SS.Pkhd1 were greatest at this timepoint. To account for genetic strain differences that do not contribute to ARPKD severity, gene expression of each cystic rat strain was compared to its parental strain.

Dataset Information

Amelioration of Sardinian beta0 thalassemia by genetic modifiers.

Publications

Amelioration of Sardinian beta0 thalassemia by genetic modifiers.

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