Mutations in multiple PKD genes may explain early and severe polycystic kidney disease.
Autosomal dominant polycystic kidney disease (ADPKD) is typically a late-onset disease caused by mutations in PKD1 or PKD2, but about 2% of patients with ADPKD show an early and severe phenotype that can be clinically indistinguishable from autosomal recessive polycystic kidney disease (ARPKD). The high recurrence risk in pedigrees with early and severe PKD strongly suggests a common familial modifying background, but the mechanisms underlying the extensive phenotypic variability observed among affected family members remain unknown. Here, we describe severely affected patients with PKD who carry, in addition to their expected familial germ-line defect, additional mutations in PKD genes, including HNF-1β, which likely aggravate the phenotype. Our findings are consistent with a common pathogenesis and dosage theory for PKD and may propose a general concept for the modification of disease expression in other so-called monogenic disorders.
Center for Human Genetics, Bioscientia, Konrad-Adenauer-Str. 17, 55218 Ingelheim, Germany. carsten.bergmann@bioscientia.de
Carsten
C
Bergmann
Jennifer
J
von Bothmer
Nadina
N
Ortiz Brüchle
Andreas
A
Venghaus
Valeska
V
Frank
Henry
H
Fehrenbach
Tobias
T
Hampel
Lars
L
Pape
Annegret
A
Buske
Jon
J
Jonsson
Nanette
N
Sarioglu
Antónia
A
Santos
Jose Carlos
JC
Ferreira
Jan U
JU
Becker
Reinhold
R
Cremer
Julia
J
Hoefele
Marcus R
MR
Benz
Lutz T
LT
Weber
Reinhard
R
Buettner
Klaus
K
Zerres
D000328:Adult; D017668:Age of Onset; D000368:Aged; D000595:Amino Acid Sequence; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics*; D005192:Family Health; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D010641:Phenotype; D016891:Polycystic Kidney, Autosomal Dominant / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D011247:Pregnancy; D012307:Risk Factors; D012720:Severity of Illness Index; D050396:TRPP Cation Channels / Q000235:genetics*
D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D050396:TRPP Cation Channels; C497396:ARNT protein, human