@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 {407,
	title = {Digenic mutations of human  paralogs in Dent{\textquoteright}s disease type 2 associated with Chiari I malformation.},
	journal = {Hum Genome Var},
	volume = {3},
	year = {2016},
	month = {2016},
	pages = {16042},
	abstract = {<p> and its paralog  encode phosphatidylinositol 5-phosphatases that localize to the primary cilium and have roles in ciliogenesis. Mutations in  cause the X-linked Dent disease type 2 (DD2; OMIM$\#$ 300555), characterized by low-molecular weight proteinuria, hypercalciuria, and the variable presence of cataracts, glaucoma and intellectual disability without structural brain anomalies. Disease-causing mutations in  have not been described in humans. Here, we report the case of an 11-year-old boy with short stature and an above-average IQ; severe proteinuria, hypercalciuria and osteopenia resulting in a vertebral compression fracture; and Chiari I malformation with cervico-thoracic syringohydromyelia requiring suboccipital decompression. Sequencing revealed a novel,  DD2-causing 462 bp deletion disrupting exon 3 of  and a maternally inherited, extremely rare (ExAC allele frequency 8.4{\texttimes}10) damaging missense mutation in  (p.A51V). This mutation substitutes an evolutionarily conserved amino acid in the protein{\textquoteright}s critical PH domain.  analyses of mutation impact predicted by SIFT, PolyPhen2, MetaSVM and CADD algorithms were all highly deleterious. Together, our findings report a novel association of DD2 with Chiari I malformation and syringohydromyelia, and document the effects of digenic mutation of human  paralogs. These findings lend genetic support to the hypothesis that impaired ciliogenesis may contribute to the development of Chiari I malformation, and implicates OCRL-dependent PIP metabolism in this mechanism.</p>},
	issn = {2054-345X},
	doi = {10.1038/hgv.2016.42},
	author = {Duran, Daniel and Jin, Sheng Chih and DeSpenza, Tyrone and Nelson-Williams, Carol and Cogal, Andrea G and Abrash, Elizabeth W and Harris, Peter C and Lieske, John C and Shimshak, Serena Je and Mane, Shrikant and Bilguvar, Kaya and DiLuna, Michael L and G{\"u}nel, Murat and Lifton, Richard P and Kahle, Kristopher T}
}
