@article {651, title = {Dominant PAX2 mutations may cause steroid-resistant nephrotic syndrome and FSGS in children.}, journal = {Pediatr Nephrol}, volume = {34}, year = {2019}, month = {2019 Sep}, pages = {1607-1613}, abstract = {

BACKGROUND: Heterozygous PAX2 mutations cause renal coloboma syndrome (RCS) [OMIM no. 120330]. RCS is a renal syndromic disease encompassing retinal coloboma and sensorineural hearing loss. Recently, a causative role for PAX2 was reported in adult-onset nephrotic syndrome secondary to focal segmental glomerulosclerosis (FSGS). However, the prevalence of PAX2 mutations among large cohort of children with steroid-resistant nephrotic syndrome (SRNS) and FSGS has not been systematically studied.

METHODS: We employed whole-exome sequencing (WES) to identify the percentage of SRNS cases explained by monogenic mutations in known genes of SRNS/FSGS. As PAX2 mutations are not an established cause of childhood FSGS, we evaluated a cohort of 215 unrelated families with SRNS, in whom no underlying genetic etiology had been previously established.

RESULTS: Using WES, we identified 3 novel causative heterozygous PAX2 mutations in 3 out of the 215 unrelated index cases studied (1.3\%). All three cases were detected in individuals from families with more than one affected and compatible with an autosomal dominant mode of inheritance (3/57 familial cases studied (5.2\%)). The clinical diagnosis in three out of four pediatric index patients was done during routine medical evaluation.

CONCLUSIONS: Our findings demonstrate high frequency of PAX2 mutations in familial form of SRNS (5.2\%) and further expand the phenotypic spectrum of PAX2 heterozygous mutations to include autosomal dominant childhood-onset FSGS. These results highlight the importance of including PAX2 in the list of genes known to cause FSGS in children.

}, issn = {1432-198X}, doi = {10.1007/s00467-019-04256-0}, author = {Vivante, Asaf and Chacham, Orna Staretz and Shril, Shirlee and Schreiber, Ruth and Mane, Shrikant M and Pode-Shakked, Ben and Soliman, Neveen A and Koneth, Irene and Schiffer, Mario and Anikster, Yair and Hildebrandt, Friedhelm} } @article {689, title = {Novel homozygous ENPP1 mutation causes generalized arterial calcifications of infancy, thrombocytopenia, and cardiovascular and central nervous system syndrome.}, journal = {Am J Med Genet A}, volume = {179}, year = {2019}, month = {2019 Oct}, pages = {2112-2118}, abstract = {

Generalized arterial calcifications of infancy (GACI) is caused by mutations in ENPP1. Other ENPP1-related phenotypes include pseudoxanthoma elasticum, hypophosphatemic rickets, and Cole disease. We studied four children from two Bedouin consanguineous families who presented with severe clinical phenotype including thrombocytopenia, hypoglycemia, hepatic, and neurologic manifestations. Initial working diagnosis included congenital infection; however, patients remained without a definitive diagnosis despite extensive workup. Consequently, we investigated a potential genetic etiology. Whole exome sequencing (WES) was performed for affected children and their parents. Following the identification of a novel mutation in the ENPP1 gene, we characterized this novel multisystemic presentation and revised relevant imaging studies. Using WES, we identified a novel homozygous mutation (c.556G > C; p.Gly186Arg) in ENPP1 which affects a highly conserved protein domain (somatomedin B2). ENPP1-associated genetic diseases exhibit phenotypic heterogeneity depending on mutation type and location. Follow-up clinical characterization of these families allowed us to revise and detect new features of systemic calcifications, which established the diagnosis of GACI, expanding the phenotypic spectrum associated with ENPP1 mutations. Our findings demonstrate that this novel ENPP1 founder mutation can cause a fatal multisystemic phenotype, mimicking severe congenital infection. This also represents the first reported mutation affecting the SMB2 domain, associated with GACI.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61334}, author = {Staretz-Chacham, Orna and Shukrun, Rachel and Barel, Ortal and Pode-Shakked, Ben and Pleniceanu, Oren and Anikster, Yair and Shalva, Nechama and Ferreira, Carlos R and Ben-Haim Kadosh, Admit and Richardson, Justin and Mane, Shrikant M and Hildebrandt, Friedhelm and Vivante, Asaf} } @article {401, title = {A Dominant Mutation in Nuclear Receptor Interacting Protein 1 Causes Urinary Tract Malformations Dysregulation of Retinoic Acid Signaling.}, journal = {J Am Soc Nephrol}, volume = {28}, year = {2017}, month = {2017 Aug}, pages = {2364-2376}, abstract = {

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of CKD in the first three decades of life. However, for most patients with CAKUT, the causative mutation remains unknown. We identified a kindred with an autosomal dominant form of CAKUT. By whole-exome sequencing, we identified a heterozygous truncating mutation (c.279delG, p.Trp93fs*) of the nuclear receptor interacting protein 1 gene () in all seven affected members. encodes a nuclear receptor transcriptional cofactor that directly interacts with the retinoic acid receptors (RARs) to modulate retinoic acid transcriptional activity. Unlike wild-type NRIP1, the altered NRIP1 protein did not translocate to the nucleus, did not interact with RAR, and failed to inhibit retinoic acid-dependent transcriptional activity upon expression in HEK293 cells. Notably, we also showed that treatment with retinoic acid enhanced NRIP1 binding to RAR RNA hybridization confirmed expression in the developing urogenital system of the mouse. In explant cultures of embryonic kidney rudiments, retinoic acid stimulated expression, whereas a pan-RAR antagonist strongly reduced it. Furthermore, mice heterozygous for a null allele of showed a CAKUT-spectrum phenotype. Finally, expression and knockdown experiments in confirmed an evolutionarily conserved role for in renal development. These data indicate that dominant mutations can cause CAKUT by interference with retinoic acid transcriptional signaling, shedding light on the well documented association between abnormal vitamin A levels and renal malformations in humans, and suggest a possible gene-environment pathomechanism in this disease.

}, keywords = {Adaptor Proteins, Signal Transducing, Animals, Mice, Mutation, Nuclear Proteins, Nuclear Receptor Interacting Protein 1, Signal Transduction, Tretinoin, Urinary Tract}, issn = {1533-3450}, doi = {10.1681/ASN.2016060694}, author = {Vivante, Asaf and Mann, Nina and Yonath, Hagith and Weiss, Anna-Carina and Getwan, Maike and Kaminski, Michael M and Bohnenpoll, Tobias and Teyssier, Catherine and Chen, Jing and Shril, Shirlee and van der Ven, Amelie T and Ityel, Hadas and Schmidt, Johanna Magdalena and Widmeier, Eugen and Bauer, Stuart B and Sanna-Cherchi, Simone and Gharavi, Ali G and Lu, Weining and Magen, Daniella and Shukrun, Rachel and Lifton, Richard P and Tasic, Velibor and Stanescu, Horia C and Cavaill{\`e}s, Vincent and Kleta, Robert and Anikster, Yair and Dekel, Benjamin and Kispert, Andreas and Lienkamp, Soeren S and Hildebrandt, Friedhelm} } @article {635, title = {Exome sequencing in Jewish and Arab patients with rhabdomyolysis reveals single-gene etiology in 43\% of cases.}, journal = {Pediatr Nephrol}, volume = {32}, year = {2017}, month = {2017 Dec}, pages = {2273-2282}, abstract = {

BACKGROUND: Rhabdomyolysis is a clinical emergency that may cause acute kidney injury (AKI). It can be acquired or due to monogenic mutations. Around 60 different rare monogenic forms of rhabdomyolysis have been reported to date. In the clinical setting, identifying the underlying molecular diagnosis is challenging due to nonspecific presentation, the high number of causative genes, and current lack of data on the prevalence of monogenic forms.

METHODS: We employed whole exome sequencing (WES) to reveal the percentage of rhabdomyolysis cases explained by single-gene (monogenic) mutations in one of 58 candidate genes. We investigated a cohort of 21 unrelated families with rhabdomyolysis, in whom no underlying etiology had been previously established.

RESULTS: Using WES, we identified causative mutations in candidate genes in nine of the 21 families (43\%). We detected disease-causing mutations in eight of 58 candidate genes, grouped into the following categories: (1) disorders of fatty acid metabolism (CPT2), (2) disorders of glycogen metabolism (PFKM and PGAM2), (3) disorders of abnormal skeletal muscle relaxation and contraction (CACNA1S, MYH3, RYR1 and SCN4A), and (4) disorders of purine metabolism (AHCY).

CONCLUSIONS: Our findings demonstrate a very high detection rate for monogenic etiologies using WES and reveal broad genetic heterogeneity for rhabdomyolysis. These results highlight the importance of molecular genetic diagnostics for establishing an etiologic diagnosis. Because these patients are at risk for recurrent episodes of rhabdomyolysis and subsequent risk for AKI, WES allows adequate prophylaxis and treatment for these patients and their family members and enables a personalized medicine approach.

}, keywords = {Adolescent, Adult, Arabs, Child, Exome, Genetic Predisposition to Disease, Humans, Jews, Mutation, Rhabdomyolysis, Whole Exome Sequencing}, issn = {1432-198X}, doi = {10.1007/s00467-017-3755-8}, author = {Vivante, Asaf and Ityel, Hadas and Pode-Shakked, Ben and Chen, Jing and Shril, Shirlee and van der Ven, Amelie T and Mann, Nina and Schmidt, Johanna Magdalena and Segel, Reeval and Aran, Adi and Zeharia, Avraham and Staretz-Chacham, Orna and Bar-Yosef, Omer and Raas-Rothschild, Annick and Landau, Yuval E and Lifton, Richard P and Anikster, Yair and Hildebrandt, Friedhelm} } @article {342, title = {MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Dec 01}, pages = {1229-1244}, abstract = {

Mitochondrial fatty acid synthesis (mtFAS) is an evolutionarily conserved pathway essential for the function of the respiratory chain and several mitochondrial enzyme complexes. We report here a unique neurometabolic human disorder caused by defective mtFAS. Seven individuals from five unrelated families presented with childhood-onset dystonia, optic atrophy, and basal ganglia signal abnormalities on MRI. All affected individuals were found to harbor recessive mutations in MECR encoding the mitochondrial trans-2-enoyl-coenzyme A-reductase involved in human mtFAS. All six mutations are extremely rare in the general population, segregate with the disease in the families, and are predicted to be deleterious. The nonsense c.855T>G (p.Tyr285), c.247_250del (p.Asn83Hisfs4), and splice site c.830+2_830+3insT mutations lead to C-terminal truncation variants of MECR. The missense c.695G>A (p.Gly232Glu), c.854A>G (p.Tyr285Cys), and c.772C>T (p.Arg258Trp) mutations involve conserved amino acid residues, are located within the cofactor binding domain, and are predicted by structural analysis to have a destabilizing effect. Yeast modeling and complementation studies validated the pathogenicity of the MECR mutations. Fibroblast cell lines from affected individuals displayed reduced levels of both MECR and lipoylated proteins as well as defective respiration. These results suggest that mutations in MECR cause a distinct human disorder of the mtFAS pathway. The observation of decreased lipoylation raises the possibility of a potential therapeutic strategy.

}, keywords = {Basal Ganglia, Cells, Cultured, Child, Child, Preschool, Dystonic Disorders, Fatty Acids, Female, Fibroblasts, Genetic Complementation Test, Humans, Infant, Male, Mitochondria, Mitochondrial Diseases, Models, Molecular, Mutation, Mutation, Missense, Optic Atrophy, Oxidoreductases Acting on CH-CH Group Donors, Pedigree, RNA Splice Sites, Saccharomyces cerevisiae}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.09.021}, author = {Heimer, Gali and Ker{\"a}t{\"a}r, Juha M and Riley, Lisa G and Balasubramaniam, Shanti and Eyal, Eran and Pietik{\"a}inen, Laura P and Hiltunen, J Kalervo and Marek-Yagel, Dina and Hamada, Jeffrey and Gregory, Allison and Rogers, Caleb and Hogarth, Penelope and Nance, Martha A and Shalva, Nechama and Veber, Alvit and Tzadok, Michal and Nissenkorn, Andreea and Tonduti, Davide and Renaldo, Florence and Kraoua, Ichraf and Panteghini, Celeste and Valletta, Lorella and Garavaglia, Barbara and Cowley, Mark J and Gayevskiy, Velimir and Roscioli, Tony and Silberstein, Jonathon M and Hoffmann, Chen and Raas-Rothschild, Annick and Tiranti, Valeria and Anikster, Yair and Christodoulou, John and Kastaniotis, Alexander J and Ben-Zeev, Bruria and Hayflick, Susan J} }