共查询到20条相似文献,搜索用时 0 毫秒
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Kezhi Yan Justine Rousseau Rebecca Okashah Littlejohn Courtney Kiss Anna Lehman Jill A. Rosenfeld Constance T.R. Stumpel Alexander P.A. Stegmann Laurie Robak Fernando Scaglia Thi Tuyet Mai Nguyen He Fu Norbert F. Ajeawung Maria Vittoria Camurri Lin Li Alice Gardham Bianca Panis Mohammed Almannai Xiang-Jiao Yang 《American journal of human genetics》2017,100(1):91-104
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Tamara Paff Niki T. Loges Isabella Aprea Kaman Wu Zeineb Bakey Eric G. Haarman Johannes M.A. Daniels Erik A. Sistermans Natalija Bogunovic Gerard W. Dougherty Inga M. Höben Jörg Große-Onnebrink Anja Matter Heike Olbrich Claudius Werner Gerard Pals Miriam Schmidts Heymut Omran Dimitra Micha 《American journal of human genetics》2017,100(1):160-168
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《American journal of human genetics》2015,97(6):904-913
Meier-Gorlin syndrome (MGS) is a genetically heterogeneous primordial dwarfism syndrome known to be caused by biallelic loss-of-function mutations in one of five genes encoding pre-replication complex proteins: ORC1, ORC4, ORC6, CDT1, and CDC6. Mutations in these genes cause disruption of the origin of DNA replication initiation. To date, only an autosomal-recessive inheritance pattern has been described in individuals with this disorder, with a molecular etiology established in about three-fourths of cases. Here, we report three subjects with MGS and de novo heterozygous mutations in the 5′ end of GMNN, encoding the DNA replication inhibitor geminin. We identified two truncating mutations in exon 2 (the 1st coding exon), c.16A>T (p.Lys6∗) and c.35_38delTCAA (p.Ile12Lysfs∗4), and one missense mutation, c.50A>G (p.Lys17Arg), affecting the second-to-last nucleotide of exon 2 and possibly RNA splicing. Geminin is present during the S, G2, and M phases of the cell cycle and is degraded during the metaphase-anaphase transition by the anaphase-promoting complex (APC), which recognizes the destruction box sequence near the 5′ end of the geminin protein. All three GMNN mutations identified alter sites 5′ to residue Met28 of the protein, which is located within the destruction box. We present data supporting a gain-of-function mechanism, in which the GMNN mutations result in proteins lacking the destruction box and hence increased protein stability and prolonged inhibition of replication leading to autosomal-dominant MGS. 相似文献
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Maja Hempel Kirsten Cremer Charlotte?W. Ockeloen Klaske?D. Lichtenbelt Johanna?C. Herkert Jonas Denecke Tobias?B. Haack Alexander?M. Zink Jessica Becker Eva Wohlleber Jessika Johannsen Bader Alhaddad Rolph Pfundt Sigrid Fuchs Dagmar Wieczorek Tim?M. Strom Koen?L.I. van?Gassen Tjitske Kleefstra Christian Kubisch Hartmut Engels Davor Lessel 《American journal of human genetics》2015,97(3):493-500
CHAMP1 encodes a protein with a function in kinetochore-microtubule attachment and in the regulation of chromosome segregation, both of which are known to be important for neurodevelopment. By trio whole-exome sequencing, we have identified de novo deleterious mutations in CHAMP1 in five unrelated individuals affected by intellectual disability with severe speech impairment, motor developmental delay, muscular hypotonia, and similar dysmorphic features including short philtrum and a tented upper and everted lover lip. In addition to two frameshift and one nonsense mutations, we found an identical nonsense mutation, c.1192C>T (p.Arg398∗), in two affected individuals. All mutations, if resulting in a stable protein, are predicted to lead to the loss of the functionally important zinc-finger domains in the C terminus of the protein, which regulate CHAMP1 localization to chromosomes and the mitotic spindle, thereby providing a mechanistic understanding for their pathogenicity. We thus establish deleterious de novo mutations in CHAMP1 as a cause of intellectual disability. 相似文献
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Biallelic Mutations in FUT8 Cause a Congenital Disorder of Glycosylation with Defective Fucosylation
Bobby G. Ng Gege Xu Nandini Chandy Joan Steyermark Deepali N. Shinde Kelly Radtke Kimiyo Raymond Carlito B. Lebrilla Ali AlAsmari Sharon F. Suchy Zöe Powis Eissa Ali Faqeih Susan A. Berry David F. Kronn Hudson H. Freeze 《American journal of human genetics》2018,102(1):188-195
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David N. Herrmann Rita Horvath Janet E. Sowden Michael Gonzales Avencia Sanchez-Mejias Zhuo Guan Roger G. Whittaker Jorge L. Almodovar Maria Lane Boglarka Bansagi Angela Pyle Veronika Boczonadi Hanns Lochmüller Helen Griffin Patrick F. Chinnery Thomas E. Lloyd J. Troy Littleton Stephan Zuchner 《American journal of human genetics》2014
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David?N. Herrmann Rita Horvath Janet?E. Sowden Michael Gonzales Avencia Sanchez-Mejias Zhuo Guan Roger?G. Whittaker Jorge?L. Almodovar Maria Lane Boglarka Bansagi Angela Pyle Veronika Boczonadi Hanns Lochmüller Helen Griffin Patrick?F. Chinnery Thomas?E. Lloyd J.?Troy Littleton Stephan Zuchner 《American journal of human genetics》2014,95(3):332-339
Synaptotagmin 2 is a synaptic vesicle protein that functions as a calcium sensor for neurotransmission but has not been previously associated with human disease. Via whole-exome sequencing, we identified heterozygous missense mutations in the C2B calcium-binding domain of the gene encoding Synaptotagmin 2 in two multigenerational families presenting with peripheral motor neuron syndromes. An essential calcium-binding aspartate residue, Asp307Ala, was disrupted by a c.920A>C change in one family that presented with an autosomal-dominant presynaptic neuromuscular junction disorder resembling Lambert-Eaton myasthenic syndrome. A c.923C>T variant affecting an adjacent residue (p.Pro308Leu) produced a presynaptic neuromuscular junction defect and a dominant hereditary motor neuropathy in a second family. Characterization of the mutation homologous to the human c.920A>C variant in Drosophila Synaptotagmin revealed a dominant disruption of synaptic vesicle exocytosis using this transgenic model. These findings indicate that Synaptotagmin 2 regulates neurotransmitter release at human peripheral motor nerve terminals. In addition, mutations in the Synaptotagmin 2 C2B domain represent an important cause of presynaptic congenital myasthenic syndromes and link them with hereditary motor axonopathies. 相似文献
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Marion Failler Heon?Yung Gee Pauline Krug Kwangsic Joo Jan Halbritter Lilya Belkacem Emilie Filhol Jonathan?D. Porath Daniela?A. Braun Markus Schueler Amandine Frigo Olivier Alibeu Cécile Masson Karine Brochard Bruno Hurault?de?Ligny Robert Novo Christine Pietrement Hulya Kayserili Rémi Salomon Marie-Claire Gubler Edgar?A. Otto Corinne Antignac Joon Kim Alexandre Benmerah Friedhelm Hildebrandt Sophie Saunier 《American journal of human genetics》2014,94(6):905-914
Ciliopathies are a group of hereditary disorders associated with defects in cilia structure and function. The distal appendages (DAPs) of centrioles are involved in the docking and anchoring of the mother centriole to the cellular membrane during ciliogenesis. The molecular composition of DAPs was recently elucidated and mutations in two genes encoding DAPs components (CEP164/NPHP15, SCLT1) have been associated with human ciliopathies, namely nephronophthisis and orofaciodigital syndrome. To identify additional DAP components defective in ciliopathies, we independently performed targeted exon sequencing of 1,221 genes associated with cilia and 5 known DAP protein-encoding genes in 1,255 individuals with a nephronophthisis-related ciliopathy. We thereby detected biallelic mutations in a key component of DAP-encoding gene, CEP83, in seven families. All affected individuals had early-onset nephronophthisis and four out of eight displayed learning disability and/or hydrocephalus. Fibroblasts and tubular renal cells from affected individuals showed an altered DAP composition and ciliary defects. In summary, we have identified mutations in CEP83, another DAP-component-encoding gene, as a cause of infantile nephronophthisis associated with central nervous system abnormalities in half of the individuals. 相似文献
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Mutations in MDH2, Encoding a Krebs Cycle Enzyme,Cause Early-Onset Severe Encephalopathy 总被引:1,自引:0,他引:1
Samira Ait-El-Mkadem Manal Dayem-Quere Mirjana Gusic Annabelle Chaussenot Sylvie Bannwarth Bérengère François Emmanuelle C. Genin Konstantina Fragaki Catharina L.M. Volker-Touw Christelle Vasnier Valérie Serre Koen L.I. van Gassen Françoise Lespinasse Susan Richter Graeme Eisenhofer Cécile Rouzier Fanny Mochel Anne De Saint-Martin Véronique Paquis-Flucklinger 《American journal of human genetics》2017,100(1):151-159
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Davor Lessel Claudia Schob Sébastien Küry Margot R.F. Reijnders Tamar Harel Mohammad K. Eldomery Zeynep Coban-Akdemir Jonas Denecke Shimon Edvardson Estelle Colin Alexander P.A. Stegmann Erica H. Gerkes Marine Tessarech Dominique Bonneau Magalie Barth Thomas Besnard Benjamin Cogné Anya Revah-Politi Hans-Jürgen Kreienkamp 《American journal of human genetics》2018,102(1):196
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Emma Tham Anna Lindstrand Avni Santani Helena Malmgren Addie Nesbitt Holly?A. Dubbs Elaine?H. Zackai Michael?J. Parker Francisca Millan Kenneth Rosenbaum Golder?N. Wilson Ann Nordgren 《American journal of human genetics》2015,96(3):507-513
Through a multi-center collaboration study, we here report six individuals from five unrelated families, with mutations in KAT6A/MOZ detected by whole-exome sequencing. All five different de novo heterozygous truncating mutations were located in the C-terminal transactivation domain of KAT6A: : c.3116_3117 delCT, p.(Ser1039∗); c.3830_3831insTT, p.(Arg1278Serfs∗17); c.3879 dupA, p.(Glu1294Argfs∗19); c.4108G>T p.(Glu1370∗) and c.4292 dupT, p.(Leu1431Phefs∗8). An additional subject with a 0.23 MB microdeletion including the entire KAT6A reading frame was identified with genome-wide array comparative genomic hybridization. Finally, by detailed clinical characterization we provide evidence that heterozygous mutations in KAT6A cause a distinct intellectual disability syndrome. The common phenotype includes hypotonia, intellectual disability, early feeding and oromotor difficulties, microcephaly and/or craniosynostosis, and cardiac defects in combination with subtle facial features such as bitemporal narrowing, broad nasal tip, thin upper lip, posteriorly rotated or low-set ears, and microretrognathia. The identification of human subjects complements previous work from mice and zebrafish where knockouts of Kat6a/kat6a lead to developmental defects. NM_001099412.1相似文献
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F.?Buket Basmanav Ana-Maria Oprisoreanu Sandra?M. Pasternack Holger Thiele Günter Fritz J?rg Wenzel Leopold Gr??er Maria Wehner Sabrina Wolf Christina Fagerberg Anette Bygum Janine Altmüller Arno Rütten Laurent Parmentier Laila El?Shabrawi-Caelen Christian Hafner Peter Nürnberg Roland Kruse Susanne Schoch Sandra Hanneken Regina?C. Betz 《American journal of human genetics》2014,94(1):135-143
Dowling-Degos disease (DDD) is an autosomal-dominant genodermatosis characterized by progressive and disfiguring reticulate hyperpigmentation. We previously identified loss-of-function mutations in KRT5 but were only able to detect pathogenic mutations in fewer than half of our subjects. To identify additional causes of DDD, we performed exome sequencing in five unrelated affected individuals without mutations in KRT5. Data analysis identified three heterozygous mutations from these individuals, all within the same gene. These mutations, namely c.11G>A (p.Trp4∗), c.652C>T (p.Arg218∗), and c.798-2A>C, are within POGLUT1, which encodes protein O-glucosyltransferase 1. Further screening of unexplained cases for POGLUT1 identified six additional mutations, as well as two of the above described mutations. Immunohistochemistry of skin biopsies of affected individuals with POGLUT1 mutations showed significantly weaker POGLUT1 staining in comparison to healthy controls with strong localization of POGLUT1 in the upper parts of the epidermis. Immunoblot analysis revealed that translation of either wild-type (WT) POGLUT1 or of the protein carrying the p.Arg279Trp substitution led to the expected size of about 50 kDa, whereas the c.652C>T (p.Arg218∗) mutation led to translation of a truncated protein of about 30 kDa. Immunofluorescence analysis identified a colocalization of the WT protein with the endoplasmic reticulum and a notable aggregating pattern for the truncated protein. Recently, mutations in POFUT1, which encodes protein O-fucosyltransferase 1, were also reported to be responsible for DDD. Interestingly, both POGLUT1 and POFUT1 are essential regulators of Notch activity. Our results furthermore emphasize the important role of the Notch pathway in pigmentation and keratinocyte morphology. 相似文献
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Janson White Juliana?F. Mazzeu Alexander Hoischen Shalini?N. Jhangiani Tomasz Gambin Michele?Calijorne Alcino Samantha Penney Jorge?M. Saraiva Hanne Hove Flemming Skovby Hülya Kayserili Elicia Estrella Anneke?T. Vulto-van?Silfhout Marloes Steehouwer Donna?M. Muzny V.?Reid Sutton Richard?A. Gibbs Baylor-Hopkins Center for Mendelian Genomics James?R. Lupski Han?G. Brunner Bregje?W.M. van?Bon Claudia?M.B. Carvalho 《American journal of human genetics》2015,96(4):612-622
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