A Founder Mutation in Artemis, an SNM1-Like Protein, Causes SCID in Athabascan-Speaking Native Americans

Abstract

Athabascan SCID (SCIDA) is an autosomal recessive disorder found among Athabascan-speaking Native Americans and is manifested by the absence of both T and B cells (T−B−NK+ SCID). We previously mapped the SCIDA gene to a 6.5-cM interval on chromosome 10p. SCIDA fibroblasts were found to have defective coding joint and reduced, but precise signal joint formation during V(D)J recombination. After excluding potential candidate genes, we conducted a combined positional candidate and positional cloning approach leading to the identification of nine novel transcripts in the refined SCIDA region. One of the transcripts showed significant homology with the mouse and yeast SNM1/PSO2 and was recently reported (Artemis) to be responsible for another T−B−NK+ SCID condition (radiation sensitive SCID) in 13 patients of primarily European origin. In our evaluation of this gene, we have identified a unique nonsense mutation in 21 SCIDA patients that is closely correlated to the founder haplotypes that we had previously identified. This nonsense founder mutation results in the truncation of the deduced protein product. The wild-type construct of the primary transcript can effectively complement the defective coding joint and reduced signal joint formation in SCIDA fibroblasts. The above results indicate that this SNM1-like gene (Artemis) is the gene responsible for SCIDA. We also discovered three additional alternative exons and detected at least six alternatively spliced SCIDA variants (SCIDA-V1, 2, 3, 4, 5, and 6) coexisting with the primary transcript in trace amounts. Finally, we found that the SCIDA primary transcript (Artemis) encodes a nuclear protein.

A novel missense RAG-1 mutation results in T−B−NK+ SCID in Athabascan-speaking Dine Indians from the Canadian Northwest Territories

“…We previously demonstrated the absence of V(D)J recombination-derived coding joint with normal signal joint formation in patients with defective Artemis (SCIDA). 8,13 In contrast, this mutation in RAG-1 cannot facilitate signal or coding joint formation, indicating that the R776W RAG-1 either fails to incise DNA or completely blocks subsequent recombination steps in vivo. It appears that this single amino-acid replacement in RAG-1 (R776W) results in a nearly complete failure of V(D)J recombination and the subsequent T and B cell deficiencies and disease.…”

“…Our original linkage study mapped the SCIDA genetic defect to chromosome 10p 13 and we subsequently identified a founder mutation in Artemis as the cause of SCIDA in Navajo and Apache Native Americans. 8,14 Surprisingly, this Artemis mutation was not found in the three T À B À NK þ SCID children from two related kindreds of Dine Indians in the Canadian Northwest Territories, a linguistically and genetically related people.…”

Severe combined immunodeficiency and microcephaly in siblings with hypomorphic mutations in DNA ligase IV

“…Human SCID with increased IR sensitivity has thus far been described in patients with null mutations in the Artemis gene and is characterized by a complete absence of T and B lymphocytes [16][17][18][19]. We herein report the occurrence of a RS-SCID, characterized by a virtual absence of B lymphocytes and a residual number of T cells, associated with microcephaly in two siblings as a consequence of mutations in the V(D)J/NHEJ factor Lig4-encoding gene.…”

“…The second group is additionally characterized by increased cellular sensitivity to ionizing radiations (IR), which points to a general DNA repair deficiency [15]. This radiosensitive SCID (RS-SCID) is caused by null mutations in the V(D)J/NHEJ factor Artemis [16][17][18][19]. Given the embryonic lethality of both Lig4 and Xrcc4 KO mice one does not expect to identify patients with complete loss of function in either gene.…”

Non-homologous end-joining, a sticky affair

“…The majority of the remaining patients show hypersensitivity to ionizing radiation, because the V(D)J recombination deficiency results from a defect in NHEJ. The majority of these patients have mutations in Artemis (Moshous et al, 2001;Li et al, 2002;Kobayashi et al, 2003;Noordzij et al, 2003). The clinical phenotype of RAG1, RAG2 and Artemis-deficient patients is similar and can be mimicked in mice (Table 1).…”