Biochemistry Laboratory (LR00SP03), Bechir Hamza Children's Hospital, Bab Saadoun Square, 1007, Tunis, Tunisia.
Higher Institute of Applied Studies in Humanity Le Kef, Department of Educational Sciences, University of Jendouba, Kef, Tunisia.
Mol Genet Genomics. 2024 Jun 23;299(1):64. doi: 10.1007/s00438-024-02157-y.
Familial Hypophosphatasia presents a complex diagnostic challenge due to its wide-ranging clinical manifestations and genetic heterogeneity. This study aims to elucidate the molecular underpinnings of familial Hypophosphatasia within a Tunisian family harboring a rare c.896 T > C mutation in the ALPL gene, offering insights into genotype-phenotype correlations and potential therapeutic avenues. The study employs a comprehensive approach, integrating biochemical examination, genetic analysis, structural modeling, and functional insights to unravel the impact of this rare mutation. Genetic investigation revealed the presence of the p.Leu299Pro mutation within the ALPL gene in affected family members. This mutation is strategically positioned in proximity to both the catalytic site and the metal-binding domain, suggesting potential functional consequences. Homology modeling techniques were employed to predict the 3D structure of TNSALP, providing insights into the structural context of the mutation. Our findings suggest that the mutation may induce conformational changes in the vicinity of the catalytic site and metal-binding domain, potentially affecting substrate recognition and catalytic efficiency. Molecular dynamics simulations were instrumental in elucidating the dynamic behavior of the tissue-nonspecific alkaline phosphatase isozyme (TNSALP) in the presence of the p.Leu299Pro mutation. The simulations indicated alterations in structural flexibility near the mutation site, with potential ramifications for the enzyme's overall stability and function. These dynamic changes may influence the catalytic efficiency of TNSALP, shedding light on the molecular underpinnings of the observed clinical manifestations within the Tunisian family. The clinical presentation of affected individuals highlighted significant phenotypic heterogeneity, underscoring the complex genotype-phenotype correlations in familial Hypophosphatasia. Variability in age of onset, severity of symptoms, and radiographic features was observed, emphasizing the need for a nuanced understanding of the clinical spectrum associated with the p.Leu299Pro mutation. This study advances our understanding of familial Hypophosphatasia by delineating the molecular consequences of the p.Leu299Pro mutation in the ALPL gene. By integrating genetic, structural, and clinical analyses, we provide insights into disease pathogenesis and lay the groundwork for personalized therapeutic strategies tailored to specific genetic profiles. Our findings underscore the importance of comprehensive genetic and clinical evaluation in guiding precision medicine approaches for familial Hypophosphatasia.
家族性低磷酸血症由于其广泛的临床表现和遗传异质性，呈现出复杂的诊断挑战。本研究旨在阐明一个突尼斯家庭中家族性低磷酸血症的分子基础，该家庭携带有 ALPL 基因中罕见的 c.896 T > C 突变，为基因型-表型相关性和潜在的治疗途径提供了深入了解。该研究采用综合方法，整合生化检查、遗传分析、结构建模和功能见解，以揭示这种罕见突变的影响。遗传研究发现，受影响的家族成员中 ALPL 基因存在 p.Leu299Pro 突变。该突变位于催化位点和金属结合域附近，具有潜在的功能后果。同源建模技术用于预测 TNSALP 的 3D 结构，提供了突变结构背景的深入了解。我们的研究结果表明，该突变可能诱导催化位点和金属结合域附近的构象变化，从而可能影响底物识别和催化效率。分子动力学模拟在阐明 p.Leu299Pro 突变存在时组织非特异性碱性磷酸酶同工酶（TNSALP）的动态行为方面发挥了重要作用。模拟表明，突变部位附近的结构灵活性发生改变，这可能对酶的整体稳定性和功能产生影响。这些动态变化可能影响 TNSALP 的催化效率，为突尼斯家庭中观察到的临床表现提供了分子基础。受影响个体的临床表现强调了家族性低磷酸血症中复杂的基因型-表型相关性，突出了表型异质性。观察到发病年龄、症状严重程度和影像学特征的可变性，强调需要对与 p.Leu299Pro 突变相关的临床谱有细致的了解。本研究通过描绘 ALPL 基因中 p.Leu299Pro 突变的分子后果，加深了对家族性低磷酸血症的理解。通过整合遗传、结构和临床分析，我们深入了解了疾病发病机制，并为针对特定遗传谱的个性化治疗策略奠定了基础。我们的研究结果强调了在指导家族性低磷酸血症精准医学方法时进行全面遗传和临床评估的重要性。
