Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease
| Autor: | Sandro, Rossetti, Vickie J, Kubly, Mark B, Consugar, Katharina, Hopp, Sushmita, Roy, Sharon W, Horsley, Dominique, Chauveau, Lesley, Rees, T Martin, Barratt, William G, van't Hoff, Patrick, Niaudet, W Patrick, Niaudet, Vicente E, Torres, Peter C, Harris |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Pathology
medicine.medical_specialty TRPP Cation Channels Genotype PKD1 DNA Mutational Analysis Autosomal dominant polycystic kidney disease Gene Dosage Mutation Missense Physiology Penetrance 030204 cardiovascular system & hematology Biology Compound heterozygosity urologic and male genital diseases Article End stage renal disease 03 medical and health sciences 0302 clinical medicine medicine Polycystic kidney disease Humans Cyst Alleles 030304 developmental biology ADPKD childhood Family Health 0303 health sciences Cysts urogenital system hypomorphic allele medicine.disease female genital diseases and pregnancy complications 3. Good health Pedigree Nephrology Kidney Failure Chronic mutation Kidney disease |
| Popis: | Autosomal dominant polycystic kidney disease (ADPKD) caused by mutations in PKD1 is significantly more severe than PKD2. Typically, ADPKD presents in adulthood but is rarely diagnosed in utero with enlarged, echogenic kidneys. Somatic mutations are thought crucial for cyst development, but gene dosage is also important since animal models with hypomorphic alleles develop cysts, but are viable as homozygotes. We screened for mutations in PKD1 and PKD2 in two consanguineous families and found PKD1 missense variants predicted to be pathogenic. In one family, two siblings homozygous for R3277C developed end stage renal disease at ages 75 and 62 years, while six heterozygotes had few cysts. In the other family, the father and two children with moderate to severe disease were homozygous for N3188S. In both families homozygous disease was associated with small cysts of relatively uniform size while marked cyst heterogeneity is typical of ADPKD. In another family, one patient diagnosed in childhood was found to be a compound heterozygote for the PKD1 variants R3105W and R2765C. All three families had evidence of developmental defects of the collecting system. Three additional ADPKD families with in utero onset had a truncating mutation in trans with either R3277C or R2765C. These cases suggest the presence of incompletely penetrant PKD1 alleles. The alleles alone may result in mild cystic disease; two such alleles cause typical to severe disease; and, in combination with an inactivating allele, are associated with early onset disease. Our study indicates that the dosage of functional PKD1 protein may be critical for cyst initiation. |
| Databáze: | OpenAIRE |
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