Cid episode 1344
![cid episode 1344 cid episode 1344](https://m.media-amazon.com/images/M/MV5BZTJhNTU1NzUtYWViNy00ZjBjLThlZTYtYmFmZDJiODc3MzhmXkEyXkFqcGdeQXVyODk3NTQ0MDU@._V1_UY268_CR97,0,182,268_AL_.jpg)
Among three siblings who shared the same bi-allelic LIG4 mutations, the index patient manifested moderately severe features of LIG4 syndrome, whereas the remaining two mutated siblings were largely asymptomatic. In this manuscript we demonstrate intrafamilial phenotypic variability of LIG4 deficiency. Besides growth failure, patients mutated in XRCC4 showed neurological presentations, severe radiosensitivity, but no immunodeficiency, and no abnormalities in V(D)J recombination in particular. In particular, mutations affecting the XRCC4-binding domain are associated with “microcephalic primordial dwarfism” (MPD), resembling what recently reported also in XRCC4-deficient patients, whereas earlier truncations on one or both alleles of the LIG4 gene result in more severe phenotypes. The severity of the clinical presentation of LIG4 deficiency has been correlated with the nature and the position of the mutations. In some patients, the diagnosis of LIG4 deficiency is made even during adulthood. The fact that some patients have a more severe immunodeficiency, consistent with SCID or Omenn syndrome (OS), and present severe neurological abnormalities, while others have less pronounced immune defects and develop normally, is illustrative of the variable clinical expressivity of LIG4 syndrome. LIG4 deficiency is also associated with chromosomal instability, and an increased risk of malignancies. Patients with LIG4 deficiency manifest short stature, microcephaly, variable degrees of CID, developmental delay, pancytopenia, and severe cellular radiosensitivity. Complete absence of LIG4 function causes late embryonic lethality due to impaired neuronal development. The LIG4 syndrome (OMIM#606593) is an autosomal recessive genetic disorder caused by hypomorphic mutations in the LIG4 gene. In addition, defects of the NHEJ pathway cause increased and generalized cellular sensitivity to ionizing radiation (IR). However, defects allowing partial function may result in milder presentations of combined immunodeficiency (CID) or “leaky SCID”. Consequently, severe defects of the NHEJ pathway lead to absence of T and B cells, and manifest as severe combined immunodeficiency (SCID). The V(D)J recombination process is specific for lymphocytes and mandatory for T and B cell development. Eventually, the coding ends are ligated by DNA Ligase 4 (LIG4) and its co-factors XRCC4 and XLF. The nucleotides inserted between V and D, or V and J segments, are referred to as N1, and those introduced between D and J segments, are referred to as N2 nucleotides.
![cid episode 1344 cid episode 1344](https://bloximages.chicago2.vip.townnews.com/nonpareilonline.com/content/tncms/assets/v3/editorial/7/1d/71d3d3a0-694b-5681-9ce8-79767e9d4ad6/57abc6a21e222.image.jpg)
In particular, nucleotides resulting from asymmetric resolution of the hairpin lead to introduction of palindromic sequences (P-nucleotides), whereas additional nucleotides may be added by the enzyme terminal deoxynucleotidyl transferase (TdT). Before these are joined, nucleotides may be added or deleted at the junctions between coding elements, thus contributing further to diversity. The holoenzyme DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is then recruited to stabilize the complex and to activate the endonuclease ARTEMIS, which opens the hairpins formed at the DNA coding ends. After the Variable (V), Diversity (D), and Joining (J) elements of the T cell receptor (TCR) and immunoglobulin genes have been targeted at recombination signal sequences by the recombination-activating gene 1 (RAG1) and RAG2 endonuclease complex, DNA ends are stabilized by the Ku70 and Ku80 proteins. DNA Ligase 4 (LIG4) is a component of the ubiquitous non-homologous end-joining (NHEJ) DNA double-strand break (DSB) repair pathway that is also involved in the process of V(D)J recombination.