A novel Jk‐null allele derived from c.383T&gt;C in exon 5 of the <i>SLC14A1</i> gene

Four phenotypes have been identified in the Kidd (JK) blood group system (International Society of Blood Transfusion (ISBT) 009): Jk(a+b−), Jk(a−b+), Jk(a+b+), and Jk(a−b−). Numerous allele variants causing the Jk(a−b−) phenotype have been reported according to the ISBT allele table.1 We reported a novel c.383T>C variant (designated JK*01N.29) in exon 5 of the SLC14A1 gene in a Chinese woman, which led to the Jk-null phenotype and segregated in the family (Genbank No: PV259662). A female proband with 3 pregnancies and no transfusions was admitted for uterine fibroid surgery. The irregular antibody screening was performed using the antihuman globulin method, and all results were positive. The autocontrol was negative. After absorption with Jk(a+b−) and Jk(a−b+) cells, the proband's serum showed negative reactions with identification cells, while the eluates from both Jk(a+b−) and Jk(a−b+) cells reacted positively. Therefore, the identified antibody was determined to be anti-Jk3. The proband's erythrocytes showed no hemolysis in a 2 M urea lysis test within 30 minutes, confirming the Jk(a−b−) phenotype. SLC14A1 coding regions were PCR-amplified from the proband, parents, and offspring and subjected to Sanger sequencing. Resulting sequences were compared with the reference sequence NG_011775.4. Haplotype sequencing of the proband's SLC14A1 gene identified c.130G>A, c.383 T>C, and c.588A>G variants in the JK*A allele, while c.342-1G>A, c.588A>G, and c.838G>A variants were found in the JK*B allele. Notably, the c.342-1G>A, c.588A>G, and c.838G>A allele is novel and has been assigned the ISBT number JK*02 N.29 (Genbank No: PX427847). The c.130G>A; c.588A>G variants have been previously reported as JK*01 W.06. A novel c.383T>C variant which substitutes proline for leucine at position 128 of the encoded protein was identified. Sanger sequencing of the proband's family revealed that the proband's mother carried the c.342-1G>A; c.838G>A variants, and the proband's father and children presented the c.383 T>C variant (Figure 1). The wild-type SLC14A1 protein sequence was retrieved from the PDB database. p.Leu128 is in a transmembrane domain. DynaMut analysis predicted that wild-type Leu128 formed a hydrogen bond (H-bond) with Tyr124, established hydrophobic contacts with Phe180, and maintained hydrophobic proximity to Thr177. In contrast, the p.Leu128Pro mutation weakened the H-bond with Tyr124, disrupted interactions with Phe180 and Thr177, and induced undefined van der Waals interactions with Val69. The disruption of these key interactions likely destabilizes the urea channel's structure, thereby conferring resistance to urea lysis. Jk(a−b−) phenotype typically arises from either homozygous JKnull alleles, or dominant suppression by the In(Jk) inhibitory gene.2 The compound heterozygous variants on the JK*B allele (c.342-1G>A; c.838G>A), inherited from the mother, were insufficient to directly cause Jk(a b−) phenotype. The c.130G>A and c.588A>G variants (JK*01 W.06) are known to result in a Jk(a + weak) phenotype but not a complete loss of JK antigen expression.3 Thus, the novel c.383 T>C variant is responsible for JK antigen deficiency. According to Genome Aggregation Database 4.1.0 https://gnomad.broadinstitute.org/gene/ENSG00000141469?dataset=gnomad_r4, the novel c.383T>C variant was identified in only 1 of 1,614,048 alleles. Specifically, the single occurrence was observed in an individual of European non-Finnish descent, and it was absent in the 44,874 East Asian alleles examined. The authors have disclosed no conflicts of interest. The Institutional Ethics Committee of Tianjin Central Hospital of Obstetrics and Gynecology (2025KY048). The data that support the findings of this study are openly available in GenBank at https://www.ncbi.nlm.nih.gov/nuccore/2941218068, reference number PV259662.1.