@article {634, title = {Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Oct}, pages = {1529-1538}, abstract = {

Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.

}, keywords = {Animals, Apoptosis, Carrier Proteins, Cell Movement, CRISPR-Cas Systems, Cytoskeleton, DNA Repair, Endoplasmic Reticulum Stress, Gene Knockout Techniques, Hernia, Hiatal, Humans, Intracellular Signaling Peptides and Proteins, Metalloendopeptidases, Mice, Microcephaly, Models, Molecular, Multiprotein Complexes, Mutation, Nephrosis, Nephrotic Syndrome, Podocytes, Protein Conformation, Protein-Serine-Threonine Kinases, RNA Processing, Post-Transcriptional, RNA, Transfer, Telomere Homeostasis, Zebrafish, Zebrafish Proteins}, issn = {1546-1718}, doi = {10.1038/ng.3933}, author = {Braun, Daniela A and Rao, Jia and Mollet, Geraldine and Schapiro, David and Daugeron, Marie-Claire and Tan, Weizhen and Gribouval, Olivier and Boyer, Olivia and Revy, Patrick and Jobst-Schwan, Tilman and Schmidt, Johanna Magdalena and Lawson, Jennifer A and Schanze, Denny and Ashraf, Shazia and Ullmann, Jeremy F P and Hoogstraten, Charlotte A and Boddaert, Nathalie and Collinet, Bruno and Martin, Ga{\"e}lle and Liger, Dominique and Lovric, Svjetlana and Furlano, Monica and Guerrera, I Chiara and Sanchez-Ferras, Oraly and Hu, Jennifer F and Boschat, Anne-Claire and Sanquer, Sylvia and Menten, Bj{\"o}rn and Vergult, Sarah and De Rocker, Nina and Airik, Merlin and Hermle, Tobias and Shril, Shirlee and Widmeier, Eugen and Gee, Heon Yung and Choi, Won-Il and Sadowski, Carolin E and Pabst, Werner L and Warejko, Jillian K and Daga, Ankana and Basta, Tamara and Matejas, Verena and Scharmann, Karin and Kienast, Sandra D and Behnam, Babak and Beeson, Brendan and Begtrup, Amber and Bruce, Malcolm and Ch{\textquoteright}ng, Gaik-Siew and Lin, Shuan-Pei and Chang, Jui-Hsing and Chen, Chao-Huei and Cho, Megan T and Gaffney, Patrick M and Gipson, Patrick E and Hsu, Chyong-Hsin and Kari, Jameela A and Ke, Yu-Yuan and Kiraly-Borri, Cathy and Lai, Wai-Ming and Lemyre, Emmanuelle and Littlejohn, Rebecca Okashah and Masri, Amira and Moghtaderi, Mastaneh and Nakamura, Kazuyuki and Ozaltin, Fatih and Praet, Marleen and Prasad, Chitra and Prytula, Agnieszka and Roeder, Elizabeth R and Rump, Patrick and Schnur, Rhonda E and Shiihara, Takashi and Sinha, Manish D and Soliman, Neveen A and Soulami, Kenza and Sweetser, David A and Tsai, Wen-Hui and Tsai, Jeng-Daw and Topaloglu, Rezan and Vester, Udo and Viskochil, David H and Vatanavicharn, Nithiwat and Waxler, Jessica L and Wierenga, Klaas J and Wolf, Matthias T F and Wong, Sik-Nin and Leidel, Sebastian A and Truglio, Gessica and Dedon, Peter C and Poduri, Annapurna and Mane, Shrikant and Lifton, Richard P and Bouchard, Maxime and Kannu, Peter and Chitayat, David and Magen, Daniella and Callewaert, Bert and van Tilbeurgh, Herman and Zenker, Martin and Antignac, Corinne and Hildebrandt, Friedhelm} } @article {37, title = {Biallelic Mutations in Citron Kinase Link Mitotic Cytokinesis to Human Primary Microcephaly.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Aug 04}, pages = {501-10}, abstract = {

Cell division terminates with cytokinesis and cellular separation. Autosomal-recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by a reduction in brain and head size at birth in addition to non-progressive intellectual disability. MCPH is genetically heterogeneous, and 16 loci are known to be associated with loss-of-function mutations predominantly affecting centrosomal-associated proteins, but the multiple roles of centrosomes in cellular function has left questions about etiology. Here, we identified three families affected by homozygous missense mutations in CIT, encoding citron rho-interacting kinase (CIT), which has established roles in cytokinesis. All mutations caused substitution of conserved amino acid residues in the kinase domain and impaired kinase activity. Neural progenitors that were differentiated from induced pluripotent stem cells (iPSCs) derived from individuals with these mutations exhibited abnormal cytokinesis with delayed mitosis, multipolar spindles, and increased apoptosis, rescued by CRISPR/Cas9 genome editing. Our results highlight the importance of cytokinesis in the pathology of primary microcephaly.

}, keywords = {Alleles, Apoptosis, Centrosome, Child, Child, Preschool, Cytokinesis, Female, Genes, Recessive, Humans, Infant, Newborn, Intracellular Signaling Peptides and Proteins, Male, Microcephaly, Mitosis, Mutation, Missense, Pedigree, Protein Serine-Threonine Kinases}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.07.004}, author = {Li, Hongda and Bielas, Stephanie L and Zaki, Maha S and Ismail, Samira and Farfara, Dorit and Um, Kyongmi and Rosti, Rasim O and Scott, Eric C and Tu, Shu and Chi, Neil C and Gabriel, Stacey and Erson-Omay, Emine Z and Ercan-Sencicek, A Gulhan and Yasuno, Katsuhito and {\c C}a{\u g}layan, Ahmet Okay and Kaymak{\c c}alan, Hande and Ekici, Bar{\i}{\c s} and Bilguvar, Kaya and G{\"u}nel, Murat and Gleeson, Joseph G} } @article {86, title = {FOXE3 mutations predispose to thoracic aortic aneurysms and dissections.}, journal = {J Clin Invest}, volume = {126}, year = {2016}, month = {2016 Mar 01}, pages = {948-61}, abstract = {

The ascending thoracic aorta is designed to withstand biomechanical forces from pulsatile blood. Thoracic aortic aneurysms and acute aortic dissections (TAADs) occur as a result of genetically triggered defects in aortic structure and a dysfunctional response to these forces. Here, we describe mutations in the forkhead transcription factor FOXE3 that predispose mutation-bearing individuals to TAAD. We performed exome sequencing of a large family with multiple members with TAADs and identified a rare variant in FOXE3 with an altered amino acid in the DNA-binding domain (p.Asp153His) that segregated with disease in this family. Additional pathogenic FOXE3 variants were identified in unrelated TAAD families. In mice, Foxe3 deficiency reduced smooth muscle cell (SMC) density and impaired SMC differentiation in the ascending aorta. Foxe3 expression was induced in aortic SMCs after transverse aortic constriction, and Foxe3 deficiency increased SMC apoptosis and ascending aortic rupture with increased aortic pressure. These phenotypes were rescued by inhibiting p53 activity, either by administration of a p53 inhibitor (pifithrin-α), or by crossing Foxe3-/- mice with p53-/- mice. Our data demonstrate that FOXE3 mutations lead to a reduced number of aortic SMCs during development and increased SMC apoptosis in the ascending aorta in response to increased biomechanical forces, thus defining an additional molecular pathway that leads to familial thoracic aortic disease.

}, keywords = {Adult, Aneurysm, Dissecting, Animals, Aorta, Aortic Aneurysm, Thoracic, Apoptosis, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p21, Female, Forkhead Transcription Factors, Gene Expression, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Muscle, Smooth, Vascular, Mutation, Missense, Myocytes, Smooth Muscle, Pedigree, Tumor Suppressor Protein p53, Vascular Remodeling, Zebrafish}, issn = {1558-8238}, doi = {10.1172/JCI83778}, author = {Kuang, Shao-Qing and Medina-Martinez, Olga and Guo, Dong-Chuan and Gong, Limin and Regalado, Ellen S and Reynolds, Corey L and Boileau, Catherine and Jondeau, Guillaume and Prakash, Siddharth K and Kwartler, Callie S and Zhu, Lawrence Yang and Peters, Andrew M and Duan, Xue-Yan and Bamshad, Michael J and Shendure, Jay and Nickerson, Debbie A and Santos-Cortez, Regie L and Dong, Xiurong and Leal, Suzanne M and Majesky, Mark W and Swindell, Eric C and Jamrich, Milan and Milewicz, Dianna M} } @article {96, title = {A patient with a novel homozygous missense mutation in FTO and concomitant nonsense mutation in CETP.}, journal = {J Hum Genet}, volume = {61}, year = {2016}, month = {2016 May}, pages = {395-403}, abstract = {

The fat mass and obesity associated (FTO) gene has previously been associated with a variety of diseases and conditions, notably obesity, acute coronary syndrome and metabolic syndrome. Reports describing mutations in FTO as well as in FTO animal models have further demonstrated a role for FTO in the development of the brain and other organs. Here, we describe a patient born of consanguineous union who presented with microcephaly, developmental delay, behavioral abnormalities, dysmorphic facial features, hypotonia and other various phenotypic abnormalities. Whole-exome sequencing revealed a novel homozygous missense mutation in FTO and a nonsense mutation in the cholesteryl ester transfer protein (CETP). Exome copy number variation analysis revealed no disease-causing large duplications or deletions within coding regions. Patient{\textquoteright}s, her parents{\textquoteright} and non-related control{\textquoteright} fibroblasts were analyzed for morphologic defects, abnormal proliferation, apoptosis and transcriptome profile. We have shown that FTO is located in the nucleus of cells from each tested sample. Western blot analysis demonstrated no changes in patient FTO. Quantitative (qPCR) analysis revealed slightly decreased levels of FTO expression in patient cells compared with controls. No morphological or proliferation differences between the patient and control fibroblasts were observed. There is still much to be learned about the molecular mechanisms by which mutations in FTO contribute to such severe phenotypes.

}, keywords = {Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Apoptosis, Biopsy, Child, Preschool, Cholesterol Ester Transfer Proteins, Computational Biology, Consanguinity, DNA Copy Number Variations, DNA Mutational Analysis, Exome, Female, Gene Expression, Gene Expression Profiling, Genetic Association Studies, Genotype, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Mutation, Missense, Phenotype, Transcriptome}, issn = {1435-232X}, doi = {10.1038/jhg.2015.160}, author = {{\c C}a{\u g}layan, Ahmet O and Tuysuz, Beyhan and Co{\c s}kun, S{\"u}leyman and Quon, Jennifer and Harmanc{\i}, Akdes S and Baranoski, Jacob F and Baran, Bur{\c c}in and Erson-Omay, E Zeynep and Henegariu, Octavian and Mane, Shrikant M and Bilguvar, Kaya and Yasuno, Katsuhito and G{\"u}nel, Murat} }