دورية أكاديمية
Bi-allelic Variants in DYNC1I2 Cause Syndromic Microcephaly with Intellectual Disability, Cerebral Malformations, and Dysmorphic Facial Features.
| العنوان: | Bi-allelic Variants in DYNC1I2 Cause Syndromic Microcephaly with Intellectual Disability, Cerebral Malformations, and Dysmorphic Facial Features. |
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| المؤلفون: | Ansar M; Department of Genetic Medicine and Development, University of Geneva, 1206 Geneva, Switzerland., Ullah F; Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA; Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering, 38000 Faisalabad, Pakistan; Pakistan Institute of Engineering and Applied Sciences, 45650 Islamabad, Pakistan., Paracha SA; Institute of Basic Medical Sciences, Khyber Medical University, 25100 Peshawar, Pakistan., Adams DJ; Atlantic Health System, Goryeb Children's Hospital, Morristown, NJ 07960, USA., Lai A; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Departments of Neurology and Pediatrics, Harvard Medical School, Center for Life Sciences, Blackfan Circle, Boston, MA 02115, USA., Pais L; Medical and Population Genetics Program, Broad Institute of MIT, Cambridge, MA 02142, USA; Center for Mendelian Genomics, Harvard University, Cambridge, MA 02142, USA., Iwaszkiewicz J; Swiss Institute of Bioinformatics, Molecular Modeling Group, Batiment Genopode, Unil Sorge, 1015 Lausanne, Switzerland., Millan F; GeneDx, Gaithersburg, MD 20877, USA., Sarwar MT; Institute of Basic Medical Sciences, Khyber Medical University, 25100 Peshawar, Pakistan., Agha Z; Department of Biosciences, COMSATS University, 45500 Islamabad, Pakistan., Shah SF; Department of Medicine, KMU Institute of Medical Sciences, 26000 Kohat, Pakistan., Qaisar AA; Radiology Department, Lady Reading Hospital, 25000 Peshawar, Pakistan., Falconnet E; Department of Genetic Medicine and Development, University of Geneva, 1206 Geneva, Switzerland., Zoete V; Swiss Institute of Bioinformatics, Molecular Modeling Group, Batiment Genopode, Unil Sorge, 1015 Lausanne, Switzerland; Department of Fundamental Oncology, Lausanne University, Ludwig Institute for Cancer Research, Route de la Corniche 9A, 1066 Epalinges, Switzerland., Ranza E; Department of Genetic Medicine and Development, University of Geneva, 1206 Geneva, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland., Makrythanasis P; Department of Genetic Medicine and Development, University of Geneva, 1206 Geneva, Switzerland; Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece., Santoni FA; Department of Genetic Medicine and Development, University of Geneva, 1206 Geneva, Switzerland; Department of Endocrinology Diabetes and Metabolism, University Hospital of Lausanne, 1011 Lausanne, Switzerland., Ahmed J; Institute of Basic Medical Sciences, Khyber Medical University, 25100 Peshawar, Pakistan., Katsanis N; Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA., Walsh C; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Departments of Neurology and Pediatrics, Harvard Medical School, Center for Life Sciences, Blackfan Circle, Boston, MA 02115, USA; Medical and Population Genetics Program, Broad Institute of MIT, Cambridge, MA 02142, USA; Center for Mendelian Genomics, Harvard University, Cambridge, MA 02142, USA., Davis EE; Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA. Electronic address: erica.davis@duke.edu., Antonarakis SE; Department of Genetic Medicine and Development, University of Geneva, 1206 Geneva, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland; iGE3 Institute of Genetics and Genomics of Geneva, 1211 Geneva, Switzerland. Electronic address: stylianos.antonarakis@unige.ch. |
| المصدر: | American journal of human genetics [Am J Hum Genet] 2019 Jun 06; Vol. 104 (6), pp. 1073-1087. Date of Electronic Publication: 2019 May 09. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 0370475 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1537-6605 (Electronic) Linking ISSN: 00029297 NLM ISO Abbreviation: Am J Hum Genet Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2008- : [Cambridge, MA] : Cell Press Original Publication: Baltimore, American Society of Human Genetics. |
| مواضيع طبية MeSH: | Mutation*, Craniofacial Abnormalities/*etiology , Dyneins/*genetics , Intellectual Disability/*etiology , Intracranial Arteriovenous Malformations/*etiology , Microcephaly/*etiology , Zebrafish/*growth & development, Adult ; Alleles ; Amino Acid Sequence ; Animals ; Child, Preschool ; Craniofacial Abnormalities/pathology ; Dyneins/chemistry ; Dyneins/metabolism ; Exome ; Female ; Homozygote ; Humans ; Infant ; Intellectual Disability/pathology ; Intracranial Arteriovenous Malformations/pathology ; Male ; Microcephaly/pathology ; Pedigree ; Phenotype ; Protein Conformation ; Sequence Homology ; Exome Sequencing ; Young Adult ; Zebrafish/genetics ; Zebrafish/metabolism |
| مستخلص: | Cargo transport along the cytoplasmic microtubular network is essential for neuronal function, and cytoplasmic dynein-1 is an established molecular motor that is critical for neurogenesis and homeostasis. We performed whole-exome sequencing, homozygosity mapping, and chromosomal microarray studies in five individuals from three independent pedigrees and identified likely-pathogenic variants in DYNC1I2 (Dynein Cytoplasmic 1 Intermediate Chain 2), encoding a component of the cytoplasmic dynein 1 complex. In a consanguineous Pakistani family with three affected individuals presenting with microcephaly, severe intellectual disability, simplification of cerebral gyration, corpus callosum hypoplasia, and dysmorphic facial features, we identified a homozygous splice donor site variant (GenBank: NM_001378.2:c.607+1G>A). We report two additional individuals who have similar neurodevelopmental deficits and craniofacial features and harbor deleterious variants; one individual bears a c.740A>G (p.Tyr247Cys) change in trans with a 374 kb deletion encompassing DYNC1I2, and an unrelated individual harbors the compound-heterozygous variants c.868C>T (p.Gln290 ∗ ) and c.740A>G (p.Tyr247Cys). Zebrafish larvae subjected to CRISPR-Cas9 gene disruption or transient suppression of dync1i2a displayed significantly altered craniofacial patterning with concomitant reduction in head size. We monitored cell death and cell cycle progression in dync1i2a zebrafish models and observed significantly increased apoptosis, likely due to prolonged mitosis caused by abnormal spindle morphology, and this finding offers initial insights into the cellular basis of microcephaly. Additionally, complementation studies in zebrafish demonstrate that p.Tyr247Cys attenuates gene function, consistent with protein structural analysis. Our genetic and functional data indicate that DYNC1I2 dysfunction probably causes an autosomal-recessive microcephaly syndrome and highlight further the critical roles of the dynein-1 complex in neurodevelopment. (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.) |
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| معلومات مُعتمدة: | P41 GM103311 United States GM NIGMS NIH HHS; R01 MH106826 United States MH NIMH NIH HHS; R01 NS035129 United States NS NINDS NIH HHS; UM1 HG008900 United States HG NHGRI NIH HHS |
| فهرسة مساهمة: | Keywords: DYNC1I2; apoptosis; autosomal recessive; developmental delay; dynein; dysmorphic facial features; intellectual disability; microcephaly; mitotic spindle; zebrafish |
| المشرفين على المادة: | EC 3.6.4.2 (Dyneins) |
| تواريخ الأحداث: | Date Created: 20190514 Date Completed: 20200311 Latest Revision: 20240214 |
| رمز التحديث: | 20240214 |
| مُعرف محوري في PubMed: | PMC6556908 |
| DOI: | 10.1016/j.ajhg.2019.04.002 |
| PMID: | 31079899 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1537-6605 |
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| DOI: | 10.1016/j.ajhg.2019.04.002 |