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Abstract：
BACKGROUND: Mucopolysaccharidosis type I (MPS-I) is a rare autosomal recessive genetic lysosomal storage disorder that is caused by pathogenic variants of the α-L-iduronidase (IDUA) gene. This study aimed to identify the genetic causes of MPS-I in a Chinese patient and construct a minigene of IDUA to analyze its variants upon splicing.
METHODS: Whole-exome sequencing (WES) and Sanger sequencing were used to confirm the potential causative variants. Single-nucleotide polymorphism (SNP) array was subsequently performed to confirm uniparental disomy (UPD). Minigene assay was performed to analyze the effect on splicing of mRNA. We meanwhile explored the conservative analysis and protein homology simulation.
RESULTS: A novel homozygous splicing mutation of IDUA, c.159-9T>A, was identified in an individual presenting with overlapping features of MPS-I. Interestingly, only the father and sisters, but not the mother, carried the variant in a heterozygous state. WES and SNP array analyses validated paternal UPD on chromosome 4. Minigene splicing revealed two aberrant splicing events: exon 2 skipping and intron 1 retention. Moreover, the specific structure of the mutant protein obviously changed according to the results of the homologous model.
CONCLUSIONS: This study describes a rare autosomal recessive disorder with paternal UPD of chromosome 4 leading to the homozygosity of the IDUA splicing variant in patients with MPS-I for the first time. This study expands the variant spectrum of IDUA and provides insights into the splicing system, facilitating its enhanced diagnosis and treatment.
METHODS: Whole-exome sequencing (WES) and Sanger sequencing were used to confirm the potential causative variants. Single-nucleotide polymorphism (SNP) array was subsequently performed to confirm uniparental disomy (UPD). Minigene assay was performed to analyze the effect on splicing of mRNA. We meanwhile explored the conservative analysis and protein homology simulation.
RESULTS: A novel homozygous splicing mutation of IDUA, c.159-9T>A, was identified in an individual presenting with overlapping features of MPS-I. Interestingly, only the father and sisters, but not the mother, carried the variant in a heterozygous state. WES and SNP array analyses validated paternal UPD on chromosome 4. Minigene splicing revealed two aberrant splicing events: exon 2 skipping and intron 1 retention. Moreover, the specific structure of the mutant protein obviously changed according to the results of the homologous model.
CONCLUSIONS: This study describes a rare autosomal recessive disorder with paternal UPD of chromosome 4 leading to the homozygosity of the IDUA splicing variant in patients with MPS-I for the first time. This study expands the variant spectrum of IDUA and provides insights into the splicing system, facilitating its enhanced diagnosis and treatment.
摘要：
背景：粘多糖贮积病I型（MPS-I）是一种罕见的常染色体隐性遗传溶酶体贮积症，由α-L-艾杜糖醛酸酶（IDUA）基因的致病变异引起。本研究旨在确定中国患者MPS-I的遗传原因，并构建IDUA的小基因以分析其剪接后的变异。
方法：使用全外显子组测序（WES）和Sanger测序来确认潜在的致病变异。随后进行单核苷酸多态性(SNP)阵列以确认单亲二体性(UPD)。进行小基因测定以分析对mRNA剪接的影响。同时我们探索了保守分析和蛋白质同源性模拟。
结果：IDUA的一个新的纯合剪接突变，c.159-9T>A，在具有MPS-I重叠特征的个体中识别出有趣的是,只有父亲和姐妹，但不是母亲,在杂合状态下携带变体。WES和SNP阵列分析验证了4号染色体上的父系UPD。小基因剪接显示两个异常剪接事件：外显子2跳跃和内含子1保留。此外，根据同源模型的结果，突变蛋白的特定结构发生了明显的变化。
结论：本研究首次描述了一种罕见的4号染色体父系UPD常染色体隐性遗传疾病，导致MPS-I患者中IDUA剪接变体纯合性。这项研究扩展了IDUA的变异谱，并提供了对剪接系统的见解，促进其加强诊断和治疗。
方法：使用全外显子组测序（WES）和Sanger测序来确认潜在的致病变异。随后进行单核苷酸多态性(SNP)阵列以确认单亲二体性(UPD)。进行小基因测定以分析对mRNA剪接的影响。同时我们探索了保守分析和蛋白质同源性模拟。
结果：IDUA的一个新的纯合剪接突变，c.159-9T>A，在具有MPS-I重叠特征的个体中识别出有趣的是,只有父亲和姐妹，但不是母亲,在杂合状态下携带变体。WES和SNP阵列分析验证了4号染色体上的父系UPD。小基因剪接显示两个异常剪接事件：外显子2跳跃和内含子1保留。此外，根据同源模型的结果，突变蛋白的特定结构发生了明显的变化。
结论：本研究首次描述了一种罕见的4号染色体父系UPD常染色体隐性遗传疾病，导致MPS-I患者中IDUA剪接变体纯合性。这项研究扩展了IDUA的变异谱，并提供了对剪接系统的见解，促进其加强诊断和治疗。
