Novel Synonymous Variant in IL7R Causes Preferential Expression of the Soluble Isoform,Journal of Clinical Immunology

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Novel Synonymous Variant in IL7R Causes Preferential Expression of the Soluble Isoform
Journal of Clinical Immunology ( IF 7.2 ) Pub Date : 2024-04-08 , DOI: 10.1007/s10875-024-01688-8
Rafah Mackeh ₁ , Yasmin El Bsat ₁ , Asha Elmi ₁ , Hani Bibawi ₂ , Mohammed Yousuf Karim _{2,

3} , Amel Hassan ₄ , Bernice Lo _{1,

5}

Affiliation

Purpose

The interleukin-7 receptor (IL-7R) is primarily expressed on lymphoid cells and plays a crucial role in the development, proliferation, and survival of T cells. Autosomal recessive mutations that disrupt IL-7Rα chain expression give rise to a severe combined immunodeficiency (SCID), which is characterized by lymphopenia and a T⁻B⁺NK⁺ phenotype. The objective here was to diagnose two siblings displaying the T⁻B⁺NK⁺ SCID phenotype as initial clinical genetic testing did not detect any variants in known SCID genes.

Methods

Whole genome sequencing (WGS) was utilized to identify potential variants causing the SCID phenotype. Splicing prediction tools were employed to assess the deleterious impact of the mutation. Polymerase Chain Reaction (PCR), Sanger sequencing, flow cytometry, and ELISA were then used to validate the pathogenicity of the detected mutation.

Results

We discovered a novel homozygous synonymous mutation in the IL7R gene. Our functional studies indicate that this variant is pathogenic, causing exon 6, which encodes the transmembrane domain, to be preferentially spliced out.

Conclusion

In this study, we identified a novel rare synonymous mutation causing a loss of IL-7Rα expression at the cellular membrane. This case demonstrates the value of reanalyzing genetic data based on the clinical phenotype and highlights the significance of functional studies in determining the pathogenicity of genetic variants.

中文翻译：

IL7R 中的新同义变体导致可溶性亚型的优先表达

目的

白细胞介素 7 受体（IL-7R）主要在淋巴细胞上表达，在 T 细胞的发育、增殖和存活中起着至关重要的作用。破坏 IL-7Rα 链表达的常染色体隐性突变会导致严重的联合免疫缺陷（SCID），其特征是淋巴细胞减少和 ^T-B⁺NK⁺ 表型。这里的目的是诊断两个表现出 ^T-B+NK⁺ SCID 表型的兄弟姐妹，因为最初的临床基因检测没有在已知的 SCID 基因中检测到任何变异。