RGD Reference Report - DCLRE1C (ARTEMIS) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiency. - Rat Genome Database

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DCLRE1C (ARTEMIS) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiency.

Authors: Volk, T  Pannicke, U  Reisli, I  Bulashevska, A  Ritter, J  Bjorkman, A  Schaffer, AA  Fliegauf, M  Sayar, EH  Salzer, U  Fisch, P  Pfeifer, D  Di Virgilio, M  Cao, H  Yang, F  Zimmermann, K  Keles, S  Caliskaner, Z  Guner, SU  Schindler, D  Hammarstrom, L  Rizzi, M  Hummel, M  Pan-Hammarstrom, Q  Schwarz, K  Grimbacher, B 
Citation: Volk T, etal., Hum Mol Genet. 2015 Dec 20;24(25):7361-72. doi: 10.1093/hmg/ddv437. Epub 2015 Oct 16.
RGD ID: 11251730
Pubmed: PMID:26476407   (View Abstract at PubMed)
PMCID: PMC4664172   (View Article at PubMed Central)
DOI: DOI:10.1093/hmg/ddv437   (Journal Full-text)

Null mutations in genes involved in V(D)J recombination cause a block in B- and T-cell development, clinically presenting as severe combined immunodeficiency (SCID). Hypomorphic mutations in the non-homologous end-joining gene DCLRE1C (encoding ARTEMIS) have been described to cause atypical SCID, Omenn syndrome, Hyper IgM syndrome and inflammatory bowel disease-all with severely impaired T-cell immunity. By whole-exome sequencing, we investigated the molecular defect in a consanguineous family with three children clinically diagnosed with antibody deficiency. We identified perfectly segregating homozygous variants in DCLRE1C in three index patients with recurrent respiratory tract infections, very low B-cell numbers and serum IgA levels. In patients, decreased colony survival after irradiation, impaired proliferative response and reduced counts of naive T cells were observed in addition to a restricted T-cell receptor repertoire, increased palindromic nucleotides in the complementarity determining regions 3 and long stretches of microhomology at switch junctions. Defective V(D)J recombination was complemented by wild-type ARTEMIS protein in vitro. Subsequently, homozygous or compound heterozygous DCLRE1C mutations were identified in nine patients from the same geographic region. We demonstrate that DCLRE1C mutations can cause a phenotype presenting as only antibody deficiency. This novel association broadens the clinical spectrum associated with ARTEMIS mutations. Clinicians should consider the possibility that an immunodeficiency with a clinically mild initial presentation could be a combined immunodeficiency, so as to provide appropriate care for affected patients.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
common variable immunodeficiency  IAGP 11251730DNA:missense mutation and frameshift mutation: :p.T65I (c.194C>T), c.1669_1670insA (human)RGD 
common variable immunodeficiency  ISODCLRE1C (Homo sapiens)11251730; 11251730DNA:missense mutation and frameshift mutation: :p.T65I (c.194C>T), c.1669_1670insA (human)RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Abnormal T cell count  IAGP 11251730DNA:missense mutation and frameshift mutation: :p.T65I (c.194C>T), c.1669_1670insA RGD 
Decreased proportion of naive B cells  IAGP 11251730DNA:missense mutation and frameshift mutation: :p.T65I (c.194C>T), c.1669_1670insA RGD 
Secretory IgA deficiency  IAGP 11251730DNA:missense mutation and frameshift mutation: :p.T65I (c.194C>T), c.1669_1670insA RGD 
Objects Annotated

Genes (Rattus norvegicus)
Dclre1c  (DNA cross-link repair 1C)

Genes (Mus musculus)
Dclre1c  (DNA cross-link repair 1C)

Genes (Homo sapiens)
DCLRE1C  (DNA cross-link repair 1C)


Additional Information