title: Clinical spectrum of LIG4 deficiency is broadened with severe dysmaturity, primordial dwarfism, and neurological abnormalities.
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.
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Pediatrics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Hanna
authors.initials: H
authors.lastname: IJspeert
authors.forename: Adilia
authors.initials: A
authors.lastname: Warris
authors.forename: Michiel
authors.initials: M
authors.lastname: van der Flier
authors.forename: Ismail
authors.initials: I
authors.lastname: Reisli
authors.forename: Sevgi
authors.initials: S
authors.lastname: Keles
authors.forename: Sandra
authors.initials: S
authors.lastname: Chishimba
authors.forename: Jacques J M
authors.initials: JJ
authors.lastname: van Dongen
authors.forename: Dik C
authors.initials: DC
authors.lastname: van Gent
authors.forename: Mirjam
authors.initials: M
authors.lastname: van der Burg
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000235:genetics*; D002466:Cell Nucleolus / Q000378:metabolism; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D019066:Facies; D015870:Gene Expression; D023061:Gene Order; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010641:Phenotype; D011485:Protein Binding; D021381:Protein Transport; D013577:Syndrome
chemical_list: C000607893:LIG4 protein, human; D011088:DNA Ligases; D000072481:DNA Ligase ATP
keywords: LIG4; NHEJ; immunodeficiency; non-homologous end joining; primordial dwarfism
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