@article {545, title = {A homozygous missense variant in VWA2, encoding an interactor of the Fraser-complex, in a patient with vesicoureteral reflux.}, journal = {PLoS One}, volume = {13}, year = {2018}, month = {2018}, pages = {e0191224}, abstract = {

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause (40-50\%) of chronic kidney disease (CKD) in children. About 40 monogenic causes of CAKUT have so far been discovered. To date less than 20\% of CAKUT cases can be explained by mutations in these 40 genes. To identify additional monogenic causes of CAKUT, we performed whole exome sequencing (WES) and homozygosity mapping (HM) in a patient with CAKUT from Indian origin and consanguineous descent. We identified a homozygous missense mutation (c.1336C>T, p.Arg446Cys) in the gene Von Willebrand factor A domain containing 2 (VWA2). With immunohistochemistry studies on kidneys of newborn (P1) mice, we show that Vwa2 and Fraser extracellular matrix complex subunit 1 (Fras1) co-localize in the nephrogenic zone of the renal cortex. We identified a pronounced expression of Vwa2 in the basement membrane of the ureteric bud (UB) and derivatives of the metanephric mesenchyme (MM). By applying in vitro assays, we demonstrate that the Arg446Cys mutation decreases translocation of monomeric VWA2 protein and increases translocation of aggregated VWA2 protein into the extracellular space. This is potentially due to the additional, unpaired cysteine residue in the mutated protein that is used for intermolecular disulfide bond formation. VWA2 is a known, direct interactor of FRAS1 of the Fraser-Complex (FC). FC-encoding genes and interacting proteins have previously been implicated in the pathogenesis of syndromic and/or isolated CAKUT phenotypes in humans. VWA2 therefore constitutes a very strong candidate in the search for novel CAKUT-causing genes. Our results from in vitro experiments indicate a dose-dependent neomorphic effect of the Arg446Cys homozygous mutation in VWA2.

}, keywords = {Amino Acid Sequence, Amino Acid Substitution, Animals, Animals, Newborn, Biomarkers, Tumor, Child, Consanguinity, Conserved Sequence, Exons, Extracellular Matrix Proteins, Fraser Syndrome, Gene Expression Regulation, Developmental, Homozygote, Humans, Male, Mice, Models, Animal, Models, Molecular, Mutation, Missense, Pedigree, Sequence Homology, Amino Acid, Urogenital Abnormalities, Urogenital System, Vesico-Ureteral Reflux}, issn = {1932-6203}, doi = {10.1371/journal.pone.0191224}, author = {van der Ven, Amelie T and Kobbe, Birgit and Kohl, Stefan and Shril, Shirlee and Pogoda, Hans-Martin and Imhof, Thomas and Ityel, Hadas and Vivante, Asaf and Chen, Jing and Hwang, Daw-Yang and Connaughton, Dervla M and Mann, Nina and Widmeier, Eugen and Taglienti, Mary and Schmidt, Johanna Magdalena and Nakayama, Makiko and Senguttuvan, Prabha and Kumar, Selvin and Tasic, Velibor and Kehinde, Elijah O and Mane, Shrikant M and Lifton, Richard P and Soliman, Neveen and Lu, Weining and Bauer, Stuart B and Hammerschmidt, Matthias and Wagener, Raimund and Hildebrandt, Friedhelm} } @article {638, title = {A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome.}, journal = {Nat Commun}, volume = {8}, year = {2017}, month = {2017 07 06}, pages = {16077}, abstract = {

Multinucleate cellular syncytial formation is a hallmark of skeletal muscle differentiation. Myomaker, encoded by Mymk (Tmem8c), is a well-conserved plasma membrane protein required for myoblast fusion to form multinucleated myotubes in mouse, chick, and zebrafish. Here, we report that autosomal recessive mutations in MYMK (OMIM 615345) cause Carey-Fineman-Ziter syndrome in humans (CFZS; OMIM 254940) by reducing but not eliminating MYMK function. We characterize MYMK-CFZS as a congenital myopathy with marked facial weakness and additional clinical and pathologic features that distinguish it from other congenital neuromuscular syndromes. We show that a heterologous cell fusion assay in vitro and allelic complementation experiments in mymk knockdown and mymk zebrafish in vivo can differentiate between MYMK wild type, hypomorphic and null alleles. Collectively, these data establish that MYMK activity is necessary for normal muscle development and maintenance in humans, and expand the spectrum of congenital myopathies to include cell-cell fusion deficits.

}, keywords = {Adult, Amino Acid Sequence, Animals, Cell Fusion, Child, Disease Models, Animal, Embryo, Nonmammalian, Female, Gene Expression, Genes, Recessive, Genetic Complementation Test, Humans, Infant, Male, Membrane Proteins, Mobius Syndrome, Morphogenesis, Muscle Proteins, Muscle, Skeletal, Muscular Diseases, Mutation, Myoblasts, Pedigree, Pierre Robin Syndrome, Sequence Alignment, Sequence Homology, Amino Acid, Zebrafish, Zebrafish Proteins}, issn = {2041-1723}, doi = {10.1038/ncomms16077}, author = {Di Gioia, Silvio Alessandro and Connors, Samantha and Matsunami, Norisada and Cannavino, Jessica and Rose, Matthew F and Gilette, Nicole M and Artoni, Pietro and de Macena Sobreira, Nara Lygia and Chan, Wai-Man and Webb, Bryn D and Robson, Caroline D and Cheng, Long and Van Ryzin, Carol and Ramirez-Martinez, Andres and Mohassel, Payam and Leppert, Mark and Scholand, Mary Beth and Grunseich, Christopher and Ferreira, Carlos R and Hartman, Tyler and Hayes, Ian M and Morgan, Tim and Markie, David M and Fagiolini, Michela and Swift, Amy and Chines, Peter S and Speck-Martins, Carlos E and Collins, Francis S and Jabs, Ethylin Wang and B{\"o}nnemann, Carsten G and Olson, Eric N and Carey, John C and Robertson, Stephen P and Manoli, Irini and Engle, Elizabeth C} } @article {10, title = {MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death.}, journal = {Genome Med}, volume = {8}, year = {2016}, month = {2016 Nov 01}, pages = {106}, abstract = {

BACKGROUND: Mitochondrial presequence proteases perform fundamental functions as they process about 70~\% of all mitochondrial preproteins that are encoded in the nucleus and imported posttranslationally. The mitochondrial intermediate presequence protease MIP/Oct1, which carries out precursor processing, has not yet been established to have a role in human disease.

METHODS: Whole exome sequencing was performed on four unrelated probands with left ventricular non-compaction (LVNC), developmental delay (DD), seizures, and severe hypotonia. Proposed pathogenic variants were confirmed by Sanger sequencing or array comparative genomic hybridization. Functional analysis of the identified MIP variants was performed using the model organism Saccharomyces cerevisiae as the protein and its functions are highly conserved from yeast to human.

RESULTS: Biallelic single nucleotide variants (SNVs) or copy number variants (CNVs) in MIPEP, which encodes MIP, were present in all four probands, three of whom had infantile/childhood death. Two patients had compound heterozygous SNVs (p.L582R/p.L71Q and p.E602*/p.L306F) and one patient from a consanguineous family had a homozygous SNV (p.K343E). The fourth patient, identified through the GeneMatcher tool, a part of the Matchmaker Exchange Project, was found to have inherited a paternal SNV (p.H512D) and a maternal CNV (1.4-Mb deletion of 13q12.12) that includes MIPEP. All amino acids affected in the patients{\textquoteright} missense variants are highly conserved from yeast to human and therefore S. cerevisiae was employed for functional analysis (for p.L71Q, p.L306F, and p.K343E). The mutations p.L339F (human p.L306F) and p.K376E (human p.K343E) resulted in a severe decrease of Oct1 protease activity and accumulation of non-processed Oct1 substrates and consequently impaired viability under respiratory growth conditions. The p.L83Q (human p.L71Q) failed to localize to the mitochondria.

CONCLUSIONS: Our findings reveal for the first time the role of the mitochondrial intermediate peptidase in human disease. Loss of MIP function results in a syndrome which consists of LVNC, DD, seizures, hypotonia, and cataracts. Our approach highlights the power of data exchange and the importance of an interrelationship between clinical and research efforts for disease gene discovery.

}, keywords = {Adult, Amino Acid Sequence, Female, Genes, Recessive, Heart Defects, Congenital, Humans, Infant, Infant, Newborn, Male, Metalloendopeptidases, Muscle Hypotonia, Pedigree, Phenotype, Sequence Homology, Amino Acid, Sudden Infant Death, Syndrome}, issn = {1756-994X}, doi = {10.1186/s13073-016-0360-6}, author = {Eldomery, Mohammad K and Akdemir, Zeynep C and V{\"o}gtle, F-Nora and Charng, Wu-Lin and Mulica, Patrycja and Rosenfeld, Jill A and Gambin, Tomasz and Gu, Shen and Burrage, Lindsay C and Al Shamsi, Aisha and Penney, Samantha and Jhangiani, Shalini N and Zimmerman, Holly H and Muzny, Donna M and Wang, Xia and Tang, Jia and Medikonda, Ravi and Ramachandran, Prasanna V and Wong, Lee-Jun and Boerwinkle, Eric and Gibbs, Richard A and Eng, Christine M and Lalani, Seema R and Hertecant, Jozef and Rodenburg, Richard J and Abdul-Rahman, Omar A and Yang, Yaping and Xia, Fan and Wang, Meng C and Lupski, James R and Meisinger, Chris and Sutton, V Reid} } @article {101, title = {A novel missense variant in the PNPLA1 gene underlies congenital ichthyosis in three consanguineous families.}, journal = {J Eur Acad Dermatol Venereol}, volume = {30}, year = {2016}, month = {2016 Dec}, pages = {e210-e213}, keywords = {Amino Acid Sequence, Consanguinity, Female, Genes, Recessive, Humans, Ichthyosiform Erythroderma, Congenital, Lipase, Male, Mutation, Missense, Pakistan, Pedigree, Sequence Homology, Amino Acid}, issn = {1468-3083}, doi = {10.1111/jdv.13540}, author = {Ahmad, F and Ansar, M and Mehmood, S and Izoduwa, A and Lee, K and Nasir, A and Abrar, M and Mehmood, S and Ullah, A and Aziz, A and Smith, J D and Shendure, J and Bamshad, M J and Nicekrson, D A and Santos-Cortez, R L P and Leal, S M and Ahmad, W} } @article {213, title = {Dominant De Novo Mutations in GJA1 Cause Erythrokeratodermia Variabilis et Progressiva, without Features of Oculodentodigital Dysplasia.}, journal = {J Invest Dermatol}, volume = {135}, year = {2015}, month = {2015 Jun}, pages = {1540-1547}, abstract = {

Genetic investigation of inherited skin disorders has informed the understanding of skin self-renewal, differentiation, and barrier function. Erythrokeratodermia variabilis et progressiva (EKVP) is a rare, inherited skin disease that is characterized by transient figurate patches of erythema, localized or generalized scaling, and frequent palmoplantar keratoderma. By using exome sequencing, we show that de novo missense mutations in GJA1 (gap junction protein alpha 1) cause EKVP. The severe, progressive skin disease in EKVP subjects with GJA1 mutations is distinct from limited cutaneous findings rarely found in the systemic disorder oculodentodigital dysplasia, also caused by dominant GJA1 mutations. GJA1 encodes connexin 43 (Cx43), the most widely expressed gap junction protein. We show that the GJA1 mutations in EKVP subjects lead to disruption of Cx43 membrane localization and aggregation within the Golgi. These findings reveal a critical role for Cx43 in epidermal homeostasis, and they provide evidence of organ-specific pathobiology resulting from different mutations within GJA1.

}, keywords = {Amino Acid Sequence, Cell Membrane, Child, Child, Preschool, Connexin 43, Connexins, Craniofacial Abnormalities, Disease Progression, Erythrokeratodermia Variabilis, Exome, Eye Abnormalities, Female, Foot Deformities, Congenital, Golgi Apparatus, HeLa Cells, Humans, Immunohistochemistry, Male, Molecular Sequence Data, Mutagenesis, Site-Directed, Mutation, Phenotype, Sequence Analysis, DNA, Sequence Homology, Amino Acid, Skin Diseases, Syndactyly, Tooth Abnormalities}, issn = {1523-1747}, doi = {10.1038/jid.2014.485}, author = {Boyden, Lynn M and Craiglow, Brittany G and Zhou, Jing and Hu, Ronghua and Loring, Erin C and Morel, Kimberly D and Lauren, Christine T and Lifton, Richard P and Bilguvar, Kaya and Paller, Amy S and Choate, Keith A} } @article {236, title = {Individual exome analysis in diagnosis and management of paediatric liver failure of indeterminate aetiology.}, journal = {J Hepatol}, volume = {61}, year = {2014}, month = {2014 Nov}, pages = {1056-63}, abstract = {

BACKGROUND \& AIMS: In children with liver failure, as many as half remain of indeterminate aetiology. This hinders timely consideration of optimal treatment options. We posit that a significant subset of these children harbour known inherited metabolic liver diseases with atypical presentation or novel inborn errors of metabolism. We investigated the utility of whole-exome sequencing in three children with advanced liver disease of indeterminate aetiology.

METHODS: Patient 1 was a 10 year-old female diagnosed with Wilson disease but no detectable ATP7B mutations, and decompensated liver cirrhosis who underwent liver transplant and subsequently developed onset of neurodegenerative disease. Patient 2 was a full-term 2 day-old male with fatal acute liver failure of indeterminate aetiology. Patient 3 was an 8 year-old female with progressive syndromic cholestasis of unknown aetiology since age 3 months.

RESULTS: Unbiased whole-exome sequencing of germline DNA revealed homozygous mutations in MPV17 and SERAC1 as the disease causing genes in patient 1 and 2, respectively. This is the first demonstration of SERAC1 loss-of-function associated fatal acute liver failure. Patient 1 expands the phenotypic spectrum of the MPV17-related hepatocerebral mitochondrial DNA depletion syndrome. Patient 3 was found to have syndromic cholestasis due to bi-allelic NOTCH2 mutations.

CONCLUSIONS: Our findings validate the application of whole-exome sequencing in the diagnosis and management of children with advanced liver disease of indeterminate aetiology, with the potential to enhance optimal selection of treatment options and adequate counselling of families. Moreover, whole-exome sequencing revealed a hitherto unrecognized phenotypic spectrum of inherited metabolic liver diseases.

}, keywords = {Amino Acid Sequence, Base Sequence, Carboxylic Ester Hydrolases, Child, Cholestasis, DNA Mutational Analysis, End Stage Liver Disease, Exome, Fatal Outcome, Female, Genes, Recessive, Hepatolenticular Degeneration, Heterozygote, Homozygote, Humans, Infant, Newborn, Liver Failure, Liver Failure, Acute, Male, Membrane Proteins, Mitochondrial Proteins, Molecular Sequence Data, Pedigree, Receptor, Notch2, RNA Splice Sites, Sequence Homology, Amino Acid}, issn = {1600-0641}, doi = {10.1016/j.jhep.2014.06.038}, author = {Vilarinho, S{\'\i}lvia and Choi, Murim and Jain, Dhanpat and Malhotra, Ajay and Kulkarni, Sanjay and Pashankar, Dinesh and Phatak, Uma and Patel, Mohini and Bale, Allen and Mane, Shrikant and Lifton, Richard P and Mistry, Pramod K} } @article {255, title = {Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors.}, journal = {Nat Genet}, volume = {46}, year = {2014}, month = {2014 Jun}, pages = {613-7}, abstract = {

Adrenal tumors autonomously producing cortisol cause Cushing{\textquoteright}s syndrome. We performed exome sequencing of 25 tumor-normal pairs and identified 2 subgroups. Eight tumors (including three carcinomas) had many somatic copy number variants (CNVs) with frequent deletion of CDC42 and CDKN2A, amplification of 5q31.2 and protein-altering mutations in TP53 and RB1. Seventeen tumors (all adenomas) had no somatic CNVs or TP53 or RB1 mutations. Six of these had known gain-of-function mutations in CTNNB1 (β-catenin) or GNAS (Gαs). Six others had somatic mutations in PRKACA (protein kinase A (PKA) catalytic subunit) resulting in a p.Leu206Arg substitution. Further sequencing identified this mutation in 13 of 63 tumors (35\% of adenomas with overt Cushing{\textquoteright}s syndrome). PRKACA, GNAS and CTNNB1 mutations were mutually exclusive. Leu206 directly interacts with the regulatory subunit of PKA, PRKAR1A. Leu206Arg PRKACA loses PRKAR1A binding, increasing the phosphorylation of downstream targets. PKA activity induces cortisol production and cell proliferation, providing a mechanism for tumor development. These findings define distinct mechanisms underlying adrenal cortisol-producing tumors.

}, keywords = {Adolescent, Adrenal Gland Neoplasms, Adult, Aged, Amino Acid Sequence, Base Sequence, cdc42 GTP-Binding Protein, Cell Proliferation, Cyclic AMP-Dependent Protein Kinase Catalytic Subunits, Cyclin-Dependent Kinase Inhibitor p16, DNA Copy Number Variations, Exome, Female, Gene Deletion, Gene Dosage, HEK293 Cells, Humans, Hydrocortisone, Male, Middle Aged, Molecular Sequence Data, Mutation, Phosphorylation, Sequence Analysis, DNA, Sequence Homology, Amino Acid}, issn = {1546-1718}, doi = {10.1038/ng.2956}, author = {Goh, Gerald and Scholl, Ute I and Healy, James M and Choi, Murim and Prasad, Manju L and Nelson-Williams, Carol and Kunstman, John W and Kuntsman, John W and Korah, Reju and Suttorp, Anna-Carinna and Dietrich, Dimo and Haase, Matthias and Willenberg, Holger S and St{\r a}lberg, Peter and Hellman, Per and Akerstr{\"o}m, G{\"o}ran and Bj{\"o}rklund, Peyman and Carling, Tobias and Lifton, Richard P} } @article {282, title = {ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption.}, journal = {J Clin Invest}, volume = {123}, year = {2013}, month = {2013 Dec}, pages = {5179-89}, abstract = {

Identification of single-gene causes of steroid-resistant nephrotic syndrome (SRNS) has furthered the understanding of the pathogenesis of this disease. Here, using a combination of homozygosity mapping and whole human exome resequencing, we identified mutations in the aarF domain containing kinase 4 (ADCK4) gene in 15 individuals with SRNS from 8 unrelated families. ADCK4 was highly similar to ADCK3, which has been shown to participate in coenzyme Q10 (CoQ10) biosynthesis. Mutations in ADCK4 resulted in reduced CoQ10 levels and reduced mitochondrial respiratory enzyme activity in cells isolated from individuals with SRNS and transformed lymphoblasts. Knockdown of adck4 in zebrafish and Drosophila recapitulated nephrotic syndrome-associated phenotypes. Furthermore, ADCK4 was expressed in glomerular podocytes and partially localized to podocyte mitochondria and foot processes in rat kidneys and cultured human podocytes. In human podocytes, ADCK4 interacted with members of the CoQ10 biosynthesis pathway, including COQ6, which has been linked with SRNS and COQ7. Knockdown of ADCK4 in podocytes resulted in decreased migration, which was reversed by CoQ10 addition. Interestingly, a patient with SRNS with a homozygous ADCK4 frameshift mutation had partial remission following CoQ10 treatment. These data indicate that individuals with SRNS with mutations in ADCK4 or other genes that participate in CoQ10 biosynthesis may be treatable with CoQ10.

}, keywords = {Adolescent, Adrenal Cortex Hormones, Amino Acid Sequence, Animals, Cells, Cultured, Child, Consanguinity, Conserved Sequence, Disease Models, Animal, DNA Mutational Analysis, Drosophila Proteins, Drug Resistance, Exome, Fibroblasts, Gene Knockdown Techniques, Humans, Mitochondria, Molecular Sequence Data, Mutation, Nephrotic Syndrome, Podocytes, Protein Kinases, Rats, Sequence Alignment, Sequence Homology, Amino Acid, Ubiquinone, Young Adult, Zebrafish, Zebrafish Proteins}, issn = {1558-8238}, doi = {10.1172/JCI69000}, author = {Ashraf, Shazia and Gee, Heon Yung and Woerner, Stephanie and Xie, Letian X and Vega-Warner, Virginia and Lovric, Svjetlana and Fang, Humphrey and Song, Xuewen and Cattran, Daniel C and Avila-Casado, Carmen and Paterson, Andrew D and Nitschk{\'e}, Patrick and Bole-Feysot, Christine and Cochat, Pierre and Esteve-Rudd, Julian and Haberberger, Birgit and Allen, Susan J and Zhou, Weibin and Airik, Rannar and Otto, Edgar A and Barua, Moumita and Al-Hamed, Mohamed H and Kari, Jameela A and Evans, Jonathan and Bierzynska, Agnieszka and Saleem, Moin A and Bockenhauer, Detlef and Kleta, Robert and El Desoky, Sherif and Hacihamdioglu, Duygu O and Gok, Faysal and Washburn, Joseph and Wiggins, Roger C and Choi, Murim and Lifton, Richard P and Levy, Shawn and Han, Zhe and Salviati, Leonardo and Prokisch, Holger and Williams, David S and Pollak, Martin and Clarke, Catherine F and Pei, York and Antignac, Corinne and Hildebrandt, Friedhelm} } @article {307, title = {Mutations in KCTD1 cause scalp-ear-nipple syndrome.}, journal = {Am J Hum Genet}, volume = {92}, year = {2013}, month = {2013 Apr 04}, pages = {621-6}, abstract = {

Scalp-ear-nipple (SEN) syndrome is a rare, autosomal-dominant disorder characterized by cutis aplasia of the scalp; minor anomalies of the external ears, digits, and nails; and malformations of the breast. We used linkage analysis and exome sequencing of a multiplex family affected by SEN syndrome to identify potassium-channel tetramerization-domain-containing 1 (KCTD1) mutations that cause SEN syndrome. Evaluation of a total of ten families affected by SEN syndrome revealed KCTD1 missense mutations in each family tested. All of the mutations occurred in a KCTD1 region encoding a highly conserved bric-a-brac, tram track, and broad complex (BTB) domain that is required for transcriptional repressor activity. KCTD1 inhibits the transactivation of the transcription factor AP-2α (TFAP2A) via its BTB domain, and mutations in TFAP2A cause cutis aplasia in individuals with branchiooculofacial syndrome (BOFS), suggesting a potential overlap in the pathogenesis of SEN syndrome and BOFS. The identification of KCTD1 mutations in SEN syndrome reveals a role for this BTB-domain-containing transcriptional repressor during ectodermal development.

}, keywords = {Abnormalities, Multiple, Amino Acid Sequence, Branchio-Oto-Renal Syndrome, Ear, External, Ectodermal Dysplasia, Exome, Female, Humans, Hypospadias, Male, Molecular Sequence Data, Muscle Hypotonia, Mutation, Missense, Nipples, Pedigree, Phenotype, Protein Structure, Tertiary, Repressor Proteins, Scalp, Sequence Homology, Amino Acid}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.03.002}, author = {Marneros, Alexander G and Beck, Anita E and Turner, Emily H and McMillin, Margaret J and Edwards, Matthew J and Field, Michael and de Macena Sobreira, Nara Lygia and Perez, Ana Beatriz A and Fortes, Jose A R and Lampe, Anne K and Giovannucci Uzielli, Maria Luisa and Gordon, Christopher T and Plessis, Ghislaine and Le Merrer, Martine and Amiel, Jeanne and Reichenberger, Ernst and Shively, Kathryn M and Cerrato, Felecia and Labow, Brian I and Tabor, Holly K and Smith, Joshua D and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J} }