Mutations in the NHEJ component XRCC4 cause primordial dwarfism

Jennie E Murray, Mirjam van der Burg, Hanna IJspeert, Paula Carroll, Qian Wu, Takashi Ochi, Andrea Leitch, Edward S Miller, Boris Kysela, Alireza Jawad, Armand Bottani, Francesco Brancati, Marco Cappa, Valerie Cormier-Daire, Charu Deshpande, Eissa A Faqeih, Gail E Graham, Emmanuelle Ranza, Tom L Blundell, Andrew P JacksonGrant S Stewart, Louise S Bicknell

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)412-424
Number of pages13
JournalAmerican Journal of Human Genetics
Issue number3
Publication statusPublished - 5 Mar 2015

Bibliographical note

Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.


  • Alleles
  • Amino Acid Sequence
  • Child
  • Child, Preschool
  • DNA Breaks, Double-Stranded
  • DNA Ligase ATP
  • DNA Ligases/genetics
  • DNA-Binding Proteins/genetics
  • Dwarfism/genetics
  • Dwarfism, Pituitary/genetics
  • Electrophoresis, Gel, Pulsed-Field
  • Exome
  • Facies
  • Female
  • Humans
  • Infant
  • Male
  • Microcephaly/genetics
  • Molecular Sequence Data
  • Mutation
  • Phenotype
  • Protein Conformation
  • Severe Combined Immunodeficiency/genetics


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