Mendiola-Vidal Namibia Guadalupe, Contreras-Cubas Cecilia, Barajas-Olmos Francisco, Villafan-Bernal José Rafael, Yañez-Felix Ana Lucia, García-Ortiz Humberto, Centeno-Cruz Federico, Mendoza-Caamal Elvia, Alaez-Verson Carmen, Jiménez-Ruíz Juan Luis, Monge-Cázares Tulia, Lieberman Esther, Baca Vicente, Lezana José Luis, Martínez-Hernández Angélica, Orozco Lorena
Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Genómica, Secretaría de Salud, Tlalpan, Mexico City 14610, Mexico.
Maestría en Ciencias Médicas, Posgrado de Maestría y Doctorado en Ciencias Médicas, Odontológicas y de la Salud, Sede: Hospital General Dr. Manuel Gea González, UNAM, Coyoacán, Mexico City 04510, Mexico.
Life (Basel). 2024 Nov 7;14(11):1445. doi: 10.3390/life14111445.
Cystic fibrosis (CF) is a rare autosomal recessive disease most commonly affecting the Caucasian population. CF diagnosis can be a challenge due to the large spectrum of pathogenic variants in the CFTR gene and the effects of complex alleles. Next-generation sequencing has improved our understanding of the contribution of these complex alleles to the wide spectrum of CF clinical symptoms and to the response to medications. Herein, we studied nine CF patients from six unrelated families carrying the complex allele p.[Ile148Thr;Ile1023_Val1024del] with a frequency of 0.18%. All patients were from Central Mexico. This complex allele was found with Class I and II pathogenic variants such as p.(Phe508del), and p.(Phe1078Profs*77)]. A targeted search of a dataset of 2217 exomes from healthy individuals revealed that eight individuals (0.18%) carried the p.(Ile148Thr) variant, but only one (0.022%), who was also born in Central Mexico, was a carrier of the complex allele. These findings show an enrichment of this p.[Ile148Thr;Ile1023_Val1024del] complex allele in Mexican CF patients in this region of Mexico. Finally, protein modeling revealed that this complex allele disrupts the secondary structure of the CFTR protein and might alter the ion flow.
囊性纤维化（CF）是一种罕见的常染色体隐性疾病，最常影响白种人群体。由于CFTR基因中致病变异的范围广泛以及复杂等位基因的影响，CF的诊断可能具有挑战性。下一代测序提高了我们对这些复杂等位基因对CF广泛临床症状的贡献以及对药物反应的理解。在此，我们研究了来自六个无亲缘关系家庭的九名CF患者，他们携带频率为0.18%的复杂等位基因p.[Ile148Thr;Ile1023_Val1024del]。所有患者均来自墨西哥中部。该复杂等位基因与I类和II类致病变异如p.(Phe508del)和p.(Phe1078Profs*77)]同时存在。对来自健康个体的2217个外显子数据集进行靶向搜索发现，八名个体（0.18%）携带p.(Ile148Thr)变异，但只有一名（0.022%），同样出生于墨西哥中部，是该复杂等位基因的携带者。这些发现表明，在墨西哥该地区的CF患者中，这种p.[Ile148Thr;Ile1023_Val1024del]复杂等位基因出现富集。最后，蛋白质建模显示，这种复杂等位基因破坏了CFTR蛋白的二级结构，并可能改变离子流动。
