Uncoordinated HLA-D Gene Expression in a RFXANK-Defective Patient with MHC Class II Deficiency

Abstract

We describe the analysis of a patient, JER, presenting classical immunological features of MHC class II deficiency. Unexpectedly, some HLA transcripts (HLA-DRA, HLA-DQA, and HLA-DMA) were found to be expressed in the JER cell line at nearly wild-type levels, while HLA-DPA and the HLA-D β-chain transcripts were not detected. Gene reporter experiments confirmed the differential transcriptional activities driven by the HLA-D promoters in the JER cells. A defect in RFXANK was first suggested by genetic complementation analyses, then assessed with the demonstration of a homozygous mutation affecting a splice donor site downstream exon 4 of RFXANK. Because the severe deletion of the resulting protein cannot account for the expression of certain HLA-D genes, minor alternative transcripts of the RFXANK gene were analyzed. We thereby showed the existence of a transcript lacking exon 4, encoding a 28-aa-deleted protein that retains a transcriptional activity. Altogether, we characterize a new type of mutation in the RFXANK gene in a MHC class II-defective patient leading to an uncoordinated expression of the HLA-D genes, and propose that this phenotype is ensured by severely limited amounts of an active, although truncated RFXANK protein.

Bare lymphocyte syndrome: An opportunity to discover our immune system

“…A founder effect for the same defect was also revealed among North African families [72,73]. Besides, an interesting case of JER cell line harboring G to C mutation downstream of exon 4 had also been reported and the consequence was the truncated RFX-B and biased propensity towards the expression of MHC II haplotypes [72,74].…”

“…In one of the cases that was described, there was half the amount of normal MHC I expression while MHC II proteins (HLA DR and HLA DQ) were virtually absent. It was reported that some of the proteins like RFX-5, RFX-ANK and RFX-AP selectively control the expression of MHC I and II genes, and it is also well understood that CIITA inhibition dampens the expression of MHC I expression, so possibly, type III BLS is an aggressive form of type II BLS [74,[100][101][102]. In many instances of type II BLS, the reduction of MHC I is often noticed in conjunction with the absence of MHC II proteins [90,103].…”

The 752delG26 mutation in the RFXANK gene associated with major histocompatibility complex class II deficiency: evidence for a founder effect in the Moroccan population

“…Several studies have also shown that about half the patients have mutations affecting complementation group B and that 73% of the corresponding kindreds are of North African descent (Morocco, Algeria and Tunisia). The 752delG26 mutation in the RFXANK gene is present in 92% of affected North African kindreds, and the most frequent molecular defect identified in cases of MHC class II deficiency is RFXANK mutation [16,22,34]. However, other mutations in the RFXANK gene have been characterised in patients of different ethnic origins (French/Spanish, Italian and Turkish) [19,21,34,35].…”

Major histocompatibility complex class II expression deficiency caused by a RFXANK founder mutation: a survey of 35 patients

“…[2][3][4][5][6][7][8][9][10][11][12]14,15, Approximately two-thirds of these patients have complementation group B deficiencies, with most of the families being of North-African descent (Algeria, Morocco, and Tunisia). 2,5,7,9,10,14,18,[27][28][29]31,32,37 A recurrent mutation of the RFXANK gene, a 26-bp deletion at the boundary between intron 5 and exon 6 called I5E6-25_I5E6 ϩ 1 (also known as 752delG- 25), has been found in Ͼ 90% of NorthAfrican families and in more than one-half of all families with MHC II deficiency. 28,37 Eight other mutations in RFXANK have been described in patients of different ethnic origins (The Netherlands, Italy, France, Spain, Tunisia, Turkey, and Saudi Arabia).…”

“…28,37 Eight other mutations in RFXANK have been described in patients of different ethnic origins (The Netherlands, Italy, France, Spain, Tunisia, Turkey, and Saudi Arabia). 14,[27][28][29]31,32,40 Thirty families with group B MHC class II deficiency investigated at our center carry the I5E6-25_I5E6 ϩ 1 mutation. We investigated whether this homozygous genotype confers a homogeneous disease phenotype by studying the clinical and immunologic features of a group of 35 NorthAfrican patients originating from 30 families and carrying a homozygous I5E6-25_I5E6 ϩ 1 deletion.…”