Clinical Spectrum of LIG4 Deficiency Is Broadened with Severe Dysmaturity, Primordial Dwarfism, and Neurological Abnormalities

Hanna IJspeert, Adilia Warris, Michiel van der Flier, Ismail Reisli, Sevgi Keles, Sandra Chishimba, Jacques J M van Dongen, Dik C van Gent, Mirjam van der Burg

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Abstract

DNA double-strand break repair via non-homologous end joining (NHEJ) is involved in recombination of immunoglobulin and T-cell receptor genes. Mutations in NHEJ components result in syndromes that are characterized by microcephaly and immunodeficiency. We present a patient with lymphopenia, extreme radiosensitivity, severe dysmaturity, corpus callosum agenesis, polysyndactily, dysmorphic appearance, and erythema, which are suggestive of a new type of NHEJ deficiency. We identified two heterozygous mutations in LIG4. The p.S205LfsX29 mutation results in lack of the nuclear localization signal and appears to be a null mutation. The second mutation p.K635RfsX10 lacks the C-terminal region responsible for XRCC4 binding and LIG4 stability and activity, and therefore this mutant might be a null mutation as well or have very low residual activity. This is remarkable since Lig4 knockout mice are embryonic lethal and so far in humans no complete LIG4 deficiencies have been described. This case broadens the clinical spectrum of LIG4 deficiencies.

Original languageEnglish
Pages (from-to)1611-1614
Number of pages4
JournalHuman Mutation
Volume34
Issue number12
Early online date18 Sep 2013
DOIs
Publication statusPublished - Dec 2013

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Dwarfism
Mutation
Agenesis of Corpus Callosum
T-Cell Receptor Genes
Nuclear Localization Signals
Microcephaly
Lymphopenia
Double-Stranded DNA Breaks
Radiation Tolerance
Erythema
Knockout Mice
Genetic Recombination
Immunoglobulins

Keywords

  • LIG4
  • immunodeficiency
  • primordial dwarfism
  • non-homologous end joining
  • NHEJ

Cite this

IJspeert, H., Warris, A., van der Flier, M., Reisli, I., Keles, S., Chishimba, S., ... van der Burg, M. (2013). Clinical Spectrum of LIG4 Deficiency Is Broadened with Severe Dysmaturity, Primordial Dwarfism, and Neurological Abnormalities. Human Mutation, 34(12), 1611-1614. https://doi.org/10.1002/humu.22436

Clinical Spectrum of LIG4 Deficiency Is Broadened with Severe Dysmaturity, Primordial Dwarfism, and Neurological Abnormalities. / IJspeert, Hanna; Warris, Adilia; van der Flier, Michiel; Reisli, Ismail; Keles, Sevgi; Chishimba, Sandra; van Dongen, Jacques J M; van Gent, Dik C; van der Burg, Mirjam.

In: Human Mutation, Vol. 34, No. 12, 12.2013, p. 1611-1614.

Research output: Contribution to journalArticle

IJspeert, H, Warris, A, van der Flier, M, Reisli, I, Keles, S, Chishimba, S, van Dongen, JJM, van Gent, DC & van der Burg, M 2013, 'Clinical Spectrum of LIG4 Deficiency Is Broadened with Severe Dysmaturity, Primordial Dwarfism, and Neurological Abnormalities', Human Mutation, vol. 34, no. 12, pp. 1611-1614. https://doi.org/10.1002/humu.22436
IJspeert, Hanna ; Warris, Adilia ; van der Flier, Michiel ; Reisli, Ismail ; Keles, Sevgi ; Chishimba, Sandra ; van Dongen, Jacques J M ; van Gent, Dik C ; van der Burg, Mirjam. / Clinical Spectrum of LIG4 Deficiency Is Broadened with Severe Dysmaturity, Primordial Dwarfism, and Neurological Abnormalities. In: Human Mutation. 2013 ; Vol. 34, No. 12. pp. 1611-1614.
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