Aadam Zahra, Kechout Nadia, Barakat Abdelhamid, Chan Koon-Wing, Ben-Ali Meriem, Ben-Mustapha Imen, Zidi Fethi, Ailal Fatima, Attal Nabila, Doudou Fatouma, Abbadi Mohamed-Cherif, Kaddache Chawki, Smati Leila, Touri Nabila, Chemli Jalel, Gargah Tahar, Brini Ines, Bakhchane Amina, Charoute Hicham, Jeddane Leila, El Atiqi Sara, El Hafidi Naïma, Hida Mustapha, Saile Rachid, Alj Hanane Salih, Boukari Rachida, Bejaoui Mohamed, Najib Jilali, Barbouche Mohamed-Ridha, Lau Yu-Lung, Mellouli Fethi, Bousfiha Ahmed Aziz
Laboratory of Biology and Health URAC34-Metabolic and Immunologic pathology Research Team, Faculty of Science of BenM'sik, King Hassan II University, Casablanca, Morocco.
Institut Pasteur, Human Molecular Genetic Laboratory, Casablanca, Morocco.
J Clin Immunol. 2016 Apr;36(3):187-94. doi: 10.1007/s10875-016-0251-z. Epub 2016 Mar 1.
X-linked agammagobulinemia (XLA) is a primary immunodeficiency caused by Bruton's tyrosine kinase (BTK) gene defect. XLA patients have absent or reduced number of peripheral B cells and a profound deficiency in all immunoglobulin isotypes. This multicenter study reports the clinical, immunological and molecular features of Bruton's disease in 40 North African male patients.
Fifty male out of 63 (male and female) patients diagnosed with serum agammaglobulinemia and non detectable to less than 2% peripheral B cells were enrolled. The search for BTK gene mutations was performed for all of them by genomic DNA amplification and Sanger sequencing.
We identified 33 different mutations in the BTK gene in 40 patients including 12 missense mutations, 6 nonsense mutations, 6 splice-site mutations, 5 frameshift, 2 large deletions, one complex mutation and one in-frame deletion. Seventeen of these mutations are novel. This large series shows a lower frequency of XLA among male patients from North Africa with agammaglobulinemia and absent to low B cells compared with other international studies (63.5% vs. 85%). No strong evidence for genotype-phenotype correlation was observed.
This study adds to other reports from highly consanguineous North African populations, showing lower frequency of X-linked forms as compared to AR forms of the same primary immunodeficiency. Furthermore, a large number of novel BTK mutations were identified and could further help identify carriers for genetic counseling.
X连锁无丙种球蛋白血症(XLA)是一种由布鲁顿酪氨酸激酶(BTK)基因缺陷引起的原发性免疫缺陷病。XLA患者外周血B细胞数量缺失或减少,所有免疫球蛋白亚型均存在严重缺陷。这项多中心研究报告了40例北非男性患者布鲁顿病的临床、免疫学和分子特征。
在63例(男性和女性)诊断为血清无丙种球蛋白血症且外周血B细胞检测不到或少于2%的患者中,纳入了50例男性患者。对所有患者进行基因组DNA扩增和桑格测序,以寻找BTK基因突变。
我们在40例患者的BTK基因中鉴定出33种不同的突变,包括12种错义突变、6种无义突变、6种剪接位点突变、5种移码突变、2种大片段缺失、1种复合突变和1种框内缺失。其中17种突变是新发现的。与其他国际研究相比,这一大型队列研究显示,在患有无丙种球蛋白血症且B细胞缺失或减少的北非男性患者中,XLA的发生率较低(63.5%对85%)。未观察到基因型与表型相关性的有力证据。
本研究补充了来自高度近亲通婚的北非人群的其他报告,显示与同一原发性免疫缺陷的常染色体隐性(AR)形式相比,X连锁形式的发生率较低。此外,还鉴定出大量新的BTK突变,这可能有助于进一步识别遗传咨询的携带者。