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Background <p>Mucopolysaccharidosis (MPS) type VII is a storage disorder of autosomal recessive origin that is caused by a deficiency in a lysosomal enzyme that results in the accumulation of glycosaminoglycans and causes secondary metabolic pathway problems. It has systemic symptoms that mainly include progressive skeletal dysplasia, cardiovascular manifestations, hepatosplenomegaly, coarse facies, and many other manifestations, and cognitive decline is observed in most cases. A significant proportion of patients may present with foetal hydrops. Allelic variations in specific ethnic groups explain the higher incidence in some groups due to founder effects and/or endogamy. In Brazil, the most common variant is p.Leu176Phe. This study aimed to investigate <i>GUSB</i> gene expression in a patient with MPS VII with a new mutation (p.Leu292Pro). Additionally, this study investigated the ancestry of 5 patients with MPS VII from Brazil to understand the Amerindian, African, and European contributions.</p> Results <p>The analysis revealed varying proportions of ancestry markers in the sample of patients with MPS VII. The European contribution was more prominent and significantly different (<i>p</i> = 0.0031) from the African contribution. Relative expression analysis by the 2<sup>−ΔCT</sup> method revealed greater expression of the <i>GUSB g</i>ene in the patient with MPS VII than in the control group (CG). However, some samples from the CG group presented higher expression than did the samples from the patient with the new mutation. Relative to the comparison among threshold cycles, 2/20 samples presented significantly different CT values for the patient with MPS VII when the numbers of amplification cycles were compared. The parents of the patient also presented different values (<i>p</i> &lt; 0.05) for the amplification cycles. The in silico prediction of the new variant indicated that it affects function by modifying a highly conserved region.</p> Conclusions <p>The p.Leu176Phe mutation may have originated in Europe, as suggested in this study. There is a discrepancy between the mRNA levels of <i>GUSB</i> and the amount of beta-glucuronidase synthesized. The expression of the <i>GUSB</i> gene variant from the patient with MPS VII was within the range of the control group’s distribution in this study. The p.Leu292Pro mutation is pathogenic, but its impact on the MPS VII phenotype still needs to be fully elucidated.</p>

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Analysis of genomic ancestry and characterization of a new variant in MPS type VII

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月25日

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  • Andreza Juliana Moreira da Costa,
  • Isabel Cristina Neves de Souza,
  • Raimunda Helena Feio,
  • Laurent Ketlen Leão Viana,
  • Mislene Cisz,
  • Célio Luiz Rafaelli,
  • Franciele Barbosa Trapp,
  • Maira Graeff Burin,
  • Kristiane Michelin-Tirelli,
  • Ana Carolina Brusius-Facchin,
  • Alice Brinckmann Oliveira Netto,
  • André Salim Khayat,
  • Ney Pereira Carneiro dos Santos,
  • Roberto Giugliani,
  • Luiz Carlos Santana-da-Silva

摘要

Background

Mucopolysaccharidosis (MPS) type VII is a storage disorder of autosomal recessive origin that is caused by a deficiency in a lysosomal enzyme that results in the accumulation of glycosaminoglycans and causes secondary metabolic pathway problems. It has systemic symptoms that mainly include progressive skeletal dysplasia, cardiovascular manifestations, hepatosplenomegaly, coarse facies, and many other manifestations, and cognitive decline is observed in most cases. A significant proportion of patients may present with foetal hydrops. Allelic variations in specific ethnic groups explain the higher incidence in some groups due to founder effects and/or endogamy. In Brazil, the most common variant is p.Leu176Phe. This study aimed to investigate GUSB gene expression in a patient with MPS VII with a new mutation (p.Leu292Pro). Additionally, this study investigated the ancestry of 5 patients with MPS VII from Brazil to understand the Amerindian, African, and European contributions.

Results

The analysis revealed varying proportions of ancestry markers in the sample of patients with MPS VII. The European contribution was more prominent and significantly different (p = 0.0031) from the African contribution. Relative expression analysis by the 2−ΔCT method revealed greater expression of the GUSB gene in the patient with MPS VII than in the control group (CG). However, some samples from the CG group presented higher expression than did the samples from the patient with the new mutation. Relative to the comparison among threshold cycles, 2/20 samples presented significantly different CT values for the patient with MPS VII when the numbers of amplification cycles were compared. The parents of the patient also presented different values (p < 0.05) for the amplification cycles. The in silico prediction of the new variant indicated that it affects function by modifying a highly conserved region.

Conclusions

The p.Leu176Phe mutation may have originated in Europe, as suggested in this study. There is a discrepancy between the mRNA levels of GUSB and the amount of beta-glucuronidase synthesized. The expression of the GUSB gene variant from the patient with MPS VII was within the range of the control group’s distribution in this study. The p.Leu292Pro mutation is pathogenic, but its impact on the MPS VII phenotype still needs to be fully elucidated.