TY - JOUR
T1 - Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease
AU - Genkyst Study Group
AU - the HALT Progression of Polycystic Kidney Disease Group
AU - the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease
AU - Cornec-Le Gall, Emilie
AU - Olson, Rory J.
AU - Besse, Whitney
AU - Heyer, Christina M.
AU - Gainullin, Vladimir G.
AU - Smith, Jessica M.
AU - Audrézet, Marie Pierre
AU - Hopp, Katharina
AU - Porath, Binu
AU - Shi, Beili
AU - Baheti, Saurabh
AU - Senum, Sarah R.
AU - Arroyo, Jennifer
AU - Madsen, Charles D.
AU - Férec, Claude
AU - Joly, Dominique
AU - Jouret, François
AU - Fikri-Benbrahim, Oussamah
AU - Charasse, Christophe
AU - Coulibaly, Jean Marie
AU - Yu, Alan S.
AU - Khalili, Korosh
AU - Pei, York
AU - Somlo, Stefan
AU - Le Meur, Yannick
AU - Torres, Vicente E.
AU - Harris, Peter C.
N1 - Publisher Copyright:
© 2018 American Society of Human Genetics
PY - 2018/5/3
Y1 - 2018/5/3
N2 - Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney cysts, often resulting in end-stage renal disease (ESRD). This disorder is genetically heterogeneous with ∼7% of families genetically unresolved. We performed whole-exome sequencing (WES) in two multiplex ADPKD-like pedigrees, and we analyzed a further 591 genetically unresolved, phenotypically similar families by targeted next-generation sequencing of 65 candidate genes. WES identified a DNAJB11 missense variant (p.Pro54Arg) in two family members presenting with non-enlarged polycystic kidneys and a frameshifting change (c.166_167insTT) in a second family with small renal and liver cysts. DNAJB11 is a co-factor of BiP, a key chaperone in the endoplasmic reticulum controlling folding, trafficking, and degradation of secreted and membrane proteins. Five additional multigenerational families carrying DNAJB11 mutations were identified by the targeted analysis. The clinical phenotype was consistent in the 23 affected members, with non-enlarged cystic kidneys that often evolved to kidney atrophy; 7 subjects reached ESRD from 59 to 89 years. The lack of kidney enlargement, histologically evident interstitial fibrosis in non-cystic parenchyma, and recurring episodes of gout (one family) suggested partial phenotypic overlap with autosomal-dominant tubulointerstitial diseases (ADTKD). Characterization of DNAJB11-null cells and kidney samples from affected individuals revealed a pathogenesis associated with maturation and trafficking defects involving the ADPKD protein, PC1, and ADTKD proteins, such as UMOD. DNAJB11-associated disease is a phenotypic hybrid of ADPKD and ADTKD, characterized by normal-sized cystic kidneys and progressive interstitial fibrosis resulting in late-onset ESRD.
AB - Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney cysts, often resulting in end-stage renal disease (ESRD). This disorder is genetically heterogeneous with ∼7% of families genetically unresolved. We performed whole-exome sequencing (WES) in two multiplex ADPKD-like pedigrees, and we analyzed a further 591 genetically unresolved, phenotypically similar families by targeted next-generation sequencing of 65 candidate genes. WES identified a DNAJB11 missense variant (p.Pro54Arg) in two family members presenting with non-enlarged polycystic kidneys and a frameshifting change (c.166_167insTT) in a second family with small renal and liver cysts. DNAJB11 is a co-factor of BiP, a key chaperone in the endoplasmic reticulum controlling folding, trafficking, and degradation of secreted and membrane proteins. Five additional multigenerational families carrying DNAJB11 mutations were identified by the targeted analysis. The clinical phenotype was consistent in the 23 affected members, with non-enlarged cystic kidneys that often evolved to kidney atrophy; 7 subjects reached ESRD from 59 to 89 years. The lack of kidney enlargement, histologically evident interstitial fibrosis in non-cystic parenchyma, and recurring episodes of gout (one family) suggested partial phenotypic overlap with autosomal-dominant tubulointerstitial diseases (ADTKD). Characterization of DNAJB11-null cells and kidney samples from affected individuals revealed a pathogenesis associated with maturation and trafficking defects involving the ADPKD protein, PC1, and ADTKD proteins, such as UMOD. DNAJB11-associated disease is a phenotypic hybrid of ADPKD and ADTKD, characterized by normal-sized cystic kidneys and progressive interstitial fibrosis resulting in late-onset ESRD.
KW - ADPKD
KW - ADPLD
KW - ADTKD
KW - DNAJB11
KW - pathogenic variants
KW - renal cystic disease
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U2 - 10.1016/j.ajhg.2018.03.013
DO - 10.1016/j.ajhg.2018.03.013
M3 - Article
C2 - 29706351
AN - SCOPUS:85046156677
SN - 0002-9297
VL - 102
SP - 832
EP - 844
JO - American journal of human genetics
JF - American journal of human genetics
IS - 5
ER -