Amri Yessine, Chouchene Saoussen, Foddha Hajer, Abderahmene Amani, Kooli Ikbel, Toumi Adnen, Hadj Khalifa Kawthar, Mezrigui Rihem, Messaoud Taieb, Hassine Mohsen, Dabboubi Rym
Biochemistry Laboratory (LR00SP03), Béchir Hamza Children's Hospital, Bab Saadoun Square, Tunis, 1007, Tunisia.
Department of Educational Sciences, Higher Institute of Applied Studies in Humanity Le Kef University of Jendouba, Le Kef, Tunisia.
BMC Med Genomics. 2025 May 27;18(1):95. doi: 10.1186/s12920-025-02145-0.
Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism, recurrent infections, bleeding tendencies, and progressive neurological impairment. The syndrome is caused by mutations in the LYST gene, which plays a crucial role in lysosomal trafficking.
This study aims to characterize the molecular basis of CHS in a Tunisian patient by identifying mutations in the LYST gene and analyzing their impact on the protein function, correlating these findings with the patient's clinical presentation.
A comprehensive clinical assessment was conducted on the patient, followed by biochemical, hematological, and microbiological analyses. Additionally, LYST protein levels were quantified in the patient and their parents using an ELISA assay. Genomic DNA was extracted from the patient's blood, and Whole Exome Sequencing (WES) was performed to identify mutations in the LYST gene. The findings were confirmed through Sanger sequencing, and bioinformatic tools were employed to predict the functional consequences of the detected mutations.
The patient presented with classical symptoms of CHS, including silver hair, hypopigmented skin, recurrent infections, and neurological decline, with an unusually late onset at 18 years. ELISA results demonstrated significantly reduced LYST levels in the patient (1.8 ng/ml) compared to heterozygous parents (7.8 ng/ml and 8.1 ng/ml) and controls (9.2 ng/ml). Genetic analysis revealed a novel homozygous deletion, c.10269_10275del (p.Gly3424SerfsTer15), in the LYST gene, leading to a frameshift mutation and premature termination of the protein. Bioinformatic analysis demonstrated that this mutation leads to the deletion of five out of sven WD40 repeats in the protein's C-terminal region, which are critical for protein-protein interactions and lysosomal trafficking.
The study identifies a novel LYST mutation in a Tunisian patient with CHS, expanding the spectrum of known genetic variants associated with the disease. The findings highlight the importance of genetic screening in populations with high consanguinity and underscore the need for targeted therapies to address the molecular defects in CHS.
切迪阿克 - 希加什综合征（CHS）是一种罕见的常染色体隐性疾病，其特征为眼皮肤白化病、反复感染、出血倾向和进行性神经功能障碍。该综合征由LYST基因突变引起，LYST基因在溶酶体运输中起关键作用。
本研究旨在通过鉴定LYST基因中的突变并分析其对蛋白质功能的影响，从而确定一名突尼斯患者CHS的分子基础，并将这些发现与患者的临床表现相关联。
对患者进行了全面的临床评估，随后进行了生化、血液学和微生物学分析。此外，使用酶联免疫吸附测定（ELISA）法对患者及其父母的LYST蛋白水平进行了定量。从患者血液中提取基因组DNA，并进行全外显子组测序（WES）以鉴定LYST基因中的突变。通过桑格测序对结果进行了确认，并使用生物信息学工具预测检测到的突变的功能后果。
该患者表现出CHS的典型症状，包括白发、皮肤色素减退症、反复感染和神经功能衰退，发病时间异常晚，为18岁。ELISA结果显示，与杂合子父母（分别为7.8 ng/ml和8.1 ng/ml）及对照组（9.2 ng/ml）相比，患者的LYST水平显著降低（1.8 ng/ml）。基因分析揭示了LYST基因中一个新的纯合缺失，即c.10269_10275del（p.Gly3424SerfsTer15），导致移码突变和蛋白质的过早终止。生物信息学分析表明，该突变导致蛋白质C末端区域七个WD40重复序列中的五个缺失，这些重复序列对于蛋白质 - 蛋白质相互作用和溶酶体运输至关重要。
本研究在一名患有CHS的突尼斯患者中鉴定出一种新的LYST突变，扩大了与该疾病相关的已知基因变异谱。这些发现突出了在高近亲结婚人群中进行基因筛查的重要性，并强调了针对CHS分子缺陷进行靶向治疗的必要性。
