@article {496,
	title = {Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease.},
	journal = {Am J Hum Genet},
	volume = {102},
	year = {2018},
	month = {2018 05 03},
	pages = {832-844},
	abstract = {<p>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.</p>},
	keywords = {Adult, Aged, Aged, 80 and over, Alleles, Amino Acid Sequence, Base Sequence, Epithelial Cells, Family, Female, HSP40 Heat-Shock Proteins, Humans, Loop of Henle, Male, Middle Aged, Mutation, Pedigree, Polycystic Kidney, Autosomal Dominant, TRPP Cation Channels, Uromodulin, Whole Exome Sequencing, Young Adult},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2018.03.013},
	author = {Cornec-Le Gall, Emilie and Olson, Rory J and Besse, Whitney and Heyer, Christina M and Gainullin, Vladimir G and Smith, Jessica M and Audr{\'e}zet, Marie-Pierre and Hopp, Katharina and Porath, Binu and Shi, Beili and Baheti, Saurabh and Senum, Sarah R and Arroyo, Jennifer and Madsen, Charles D and F{\'e}rec, Claude and Joly, Dominique and Jouret, Fran{\c c}ois and Fikri-Benbrahim, Oussamah and Charasse, Christophe and Coulibaly, Jean-Marie and Yu, Alan S and Khalili, Korosh and Pei, York and Somlo, Stefan and Le Meur, Yannick and Torres, Vicente E and Harris, Peter C}
}
@article {135,
	title = {Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy.},
	journal = {Cell Rep},
	volume = {12},
	year = {2015},
	month = {2015 Aug 18},
	pages = {1169-83},
	abstract = {<p>Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in \~{} 45\% (17/37) of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy-associated genes in subjects versus controls, confirmed in a second ethnically discrete neuropathy cohort, suggesting that mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HPMVs) and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest that the combinatorial effect of rare variants contributes to disease burden and variable expressivity.</p>},
	keywords = {Animals, Charcot-Marie-Tooth Disease, Exome, Female, Genetic Load, Genetic Variation, HSP40 Heat-Shock Proteins, Humans, Male, Mutation, Myelin P2 Protein, Pedigree, Penetrance, Peripheral Nervous System Diseases, Phenotype, Serine C-Palmitoyltransferase, Suppression, Genetic, Zebrafish},
	issn = {2211-1247},
	doi = {10.1016/j.celrep.2015.07.023},
	author = {Gonzaga-Jauregui, Claudia and Harel, Tamar and Gambin, Tomasz and Kousi, Maria and Griffin, Laurie B and Francescatto, Ludmila and Ozes, Burcak and Karaca, Ender and Jhangiani, Shalini N and Bainbridge, Matthew N and Lawson, Kim S and Pehlivan, Davut and Okamoto, Yuji and Withers, Marjorie and Mancias, Pedro and Slavotinek, Anne and Reitnauer, Pamela J and Goksungur, Meryem T and Shy, Michael and Crawford, Thomas O and Koenig, Michel and Willer, Jason and Flores, Brittany N and Pediaditrakis, Igor and Us, Onder and Wiszniewski, Wojciech and Parman, Yesim and Antonellis, Anthony and Muzny, Donna M and Katsanis, Nicholas and Battaloglu, Esra and Boerwinkle, Eric and Gibbs, Richard A and Lupski, James R}
}
