Mutations in the NHEJ Component XRCC4 Cause Primordial Dwarfism
| Autor: | Valérie Cormier-Daire, Hanna IJspeert, Boris Kysela, Grant S. Stewart, Marco Cappa, Gail E. Graham, Mirjam van der Burg, Louise S. Bicknell, Francesco Brancati, Armand Bottani, Eissa Faqeih, Jennie E. Murray, Takashi Ochi, Emmanuelle Ranza, Alireza Jawad, Tom L. Blundell, Edward S. Miller, Andrew P. Jackson, Andrea Leitch, Charu Deshpande, Qian Wu, Paula Carroll |
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| Přispěvatelé: | Immunology |
| Rok vydání: | 2015 |
| Předmět: |
Male
Protein Conformation Dwarfism LIG4 medicine.disease_cause DNA Ligase ATP Double-Stranded 0302 clinical medicine DNA Breaks Double-Stranded Genetics(clinical) Exome Child Genetics (clinical) Genetics Gel 0303 health sciences Mutation DNA repair protein XRCC4 Acquired immune system Phenotype Electrophoresis Gel Pulsed-Field DNA-Binding Proteins Child Preschool Microcephaly Female Electrophoresis DNA Ligases Molecular Sequence Data Biology Article Pulsed-Field 03 medical and health sciences medicine Humans Amino Acid Sequence Dwarfism Pituitary Preschool Alleles 030304 developmental biology Severe combined immunodeficiency DNA Breaks fungi Facies Infant medicine.disease Pituitary Severe Combined Immunodeficiency Primordial dwarfism 030217 neurology & neurosurgery |
| Zdroj: | American Journal of Human Genetics, 96(3), 412-424. Cell Press |
| ISSN: | 0002-9297 |
| Popis: | Non-homologous end joining (NHEJ) is a key cellular process ensuring genome integrity. Mutations in several components of the NHEJ pathway have been identified, often associated with severe combined immunodeficiency (SCID), consistent with the requirement for NHEJ during V(D)J recombination to ensure diversity of the adaptive immune system. In contrast, we have recently found that biallelic mutations in LIG4 are a common cause of microcephalic primordial dwarfism (MPD), a phenotype characterized by prenatal-onset extreme global growth failure. Here we provide definitive molecular genetic evidence supported by biochemical, cellular, and immunological data for mutations in XRCC4, encoding the obligate binding partner of LIG4, causing MPD. We report the identification of biallelic mutations in XRCC4 in five families. Biochemical and cellular studies demonstrate that these alterations substantially decrease XRCC4 protein levels leading to reduced cellular ligase IV activity. Consequently, NHEJ-dependent repair of ionizing-radiation-induced DNA double-strand breaks is compromised in XRCC4 cells. Similarly, immunoglobulin junctional diversification is impaired in cells. However, immunoglobulin levels are normal, and individuals lack overt signs of immunodeficiency. Additionally, in contrast to individuals with LIG4 mutations, pancytopenia leading to bone marrow failure has not been observed. Hence, alterations that alter different NHEJ proteins give rise to a phenotypic spectrum, from SCID to extreme growth failure, with deficiencies in certain key components of this repair pathway predominantly exhibiting growth deficits, reflecting differential developmental requirements for NHEJ proteins to support growth and immune maturation. |
| Databáze: | OpenAIRE |
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