<i>IDUA</i>
            mutational profile and genotype–phenotype relationships in UK patients with Mucopolysaccharidosis Type I

Ghosh, Arunabha; Mercer, Jean; Mackinnon, Sabrina; Yue, Wyatt W.; Church, Heather J.; Beesley, Clare E.; Broomfield, Alexander; Jones, Simon A.; Tylee, Karen

doi:10.1002/humu.23301

Cited by 21 publications

(28 citation statements)

References 40 publications

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“…18,19 The HumVar score for the new substitutions was close to 1 (except for p.Ser157Pro that is 0.772), thus predicted the severe pathological effect of this mutation (Table 3). This substitution occurs near to the active site of IDUA, and in addition to gain of charge, it causes loss of main chain flexibility and also solvent available surface.…”

Section: Discussionmentioning

confidence: 87%

“…This is a rare mutation and highly effects on solvent available residues. 18,19 The HumVar score for the new substitutions was close to 1 (except for p.Ser157Pro that is 0.772), thus predicted the severe pathological effect of this mutation (Table 3). Moreover, we sequenced therefore, it explains that biochemical analysis was not significant to determine the clinical types of MPSI ( There were the following inconsistencies in genotype-phenotype correlations.…”

Section: Discussionmentioning

confidence: 87%

“…Therefore, the large variation in the mutational spectrum of the IDUA gene is possibly considered as a main cause of the clinical heterogeneity of MPSI. Many works have been done to search for genotype-phenotype correlation in patients with MPSI 19,20. Ghosh et al19 analyzed the genotype-phenotype in a cohort of 291 individuals with MPSI.…”

mentioning

confidence: 99%

“…Many works have been done to search for genotype-phenotype correlation in patients with MPSI 19,20. Ghosh et al19 analyzed the genotype-phenotype in a cohort of 291 individuals with MPSI. They assumed that a severe phenotype would be specified in the presence of two severe variants.…”

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confidence: 99%

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Mutation analysis and clinical characterization of Iranian patients with mucopolysaccharidosis type I

Taghikhani

Khatami

Abdi

et al. 2019

Clinical Laboratory Analysis

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BackgroundMucopolysaccharidosis type I (MPSI) is a rare autosomal recessive disorder caused by a deficiency of α‐l‐iduronidase (IDUA) encoded by the IDUA gene. We examined the mutation spectrum of the IDUA gene to explain the clinical, biochemical, and molecular features in 21 Iranian patients with MPSI.MethodsSanger sequencing was used to measure the IDUA gene sequence in the coding region and exon‐intron boundaries. We recorded the clinical findings of studied patients at the first diagnosis of disease and then during the treatment and follow‐up.ResultsFive different missense disease‐causing mutations were determined in our patient groups, indicating 90.48% of detection rate. The most widespread mutation was the p.Y109H, occurring in 15.625% of all alleles, which was reported for the first time in our study. Other frequent mutations were as follows: p.Ser157Pro (12.5%), p.Gly84Arg (12.5%), p.Asp257His (9.375%), and p.Asp301Glu (9.375%). Three ones of them were new missense mutations: p.Ser157Pro, p.Asp257His, and p.Asp301Glu.DiscussionThe results of this study explain the different spectrum of IDUA gene mutations in our patients with MPSI. We introduced here 32 different variants including four new variants: p.Y109H (15.625%), p.S157P (12.5%), p.D257H (9.375%), and p.D301E (9.375%). In this series, there was no relationship between the happening of clinical features and genotype variations and biochemical findings.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 87%

mentioning

confidence: 99%

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confidence: 99%

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Mutation analysis and clinical characterization of Iranian patients with mucopolysaccharidosis type I

Taghikhani

Khatami

Abdi

et al. 2019

Clinical Laboratory Analysis

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“…7 Over 200 pathogenic IDUA variants have been reported to underlie MPS I and a genotype-phenotype association is emerging whereby patients who are either homozygous or compound heterozygous for the common nonsense mutations W402X or Q70X consistently have severe disease. [14][15][16][17][18][19] The large number of patients enrolled in the MPS I Registry offers a unique resource for further elaboration of genotype/phenotype relationships for this rare disease. [20][21][22] 2 | MATERIALS AND METHODS…”

Section: Introductionmentioning

confidence: 99%

Genotype‐phenotype relationships in mucopolysaccharidosis type I (MPS I): Insights from the International MPS I Registry

et al. 2019

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Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder resulting from pathogenic variants in the α‐L‐iduronidase (IDUA) gene. Clinical phenotypes range from severe (Hurler syndrome) to attenuated (Hurler‐Scheie and Scheie syndromes) and vary in age of onset, severity, and rate of progression. Defining the phenotype at diagnosis is essential for disease management. To date, no systematic analysis of genotype‐phenotype correlation in large MPS I cohorts have been performed. Understanding genotype‐phenotype is critical now that newborn screening for MPS I is being implemented. Data from 538 patients from the MPS I Registry (380 severe, 158 attenuated) who had 2 IDUA alleles identified were examined. In the 1076 alleles identified, 148 pathogenic variants were reported; of those, 75 were unique. Of the 538 genotypes, 147 (27%) were unique; 40% of patients with attenuated and 22% of patients with severe MPS I had unique genotypes. About 67.6% of severe patients had genotypes where both variants identified are predicted to severely disrupt protein/gene function and 96.1% of attenuated patients had at least one missense or intronic variant. This dataset illustrates a close genotype/phenotype correlation in MPS I but the presence of unique IDUA missense variants remains a challenge for disease prediction.

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MPS I: Early diagnosis, bone disease and treatment, where are we now?

Kingma

Jonckheere

2021

J of Inher Metab Disea

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Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder characterized by α‐L‐iduronidase deficiency. Patients present with a broad spectrum of disease severity ranging from the most severe phenotype (Hurler) with devastating neurocognitive decline, bone disease and early death to intermediate (Hurler‐Scheie) and more attenuated (Scheie) phenotypes, with a normal life expectancy. The most severely affected patients are preferably treated with hematopoietic stem cell transplantation, which halts the neurocognitive decline. Patients with more attenuated phenotypes are treated with enzyme replacement therapy. There are several challenges to be met in the treatment of MPS I patients. First, to optimize outcome, early recognition of the disease and clinical phenotype is needed to guide decisions on therapeutic strategies. Second, there is thus far no effective treatment available for MPS I bone disease. The pathophysiological mechanisms behind bone disease are largely unknown, limiting the development of effective therapeutic strategies. This article is a state of the art that comprehensively discusses three of the most urgent open issues in MPS I: early diagnosis of MPS I patients, pathophysiology of MPS I bone disease, and emerging therapeutic strategies for MPS I bone disease.

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IDUA mutational profile and genotype–phenotype relationships in UK patients with Mucopolysaccharidosis Type I

Cited by 21 publications

References 40 publications

Mutation analysis and clinical characterization of Iranian patients with mucopolysaccharidosis type I

Mutation analysis and clinical characterization of Iranian patients with mucopolysaccharidosis type I

Genotype‐phenotype relationships in mucopolysaccharidosis type I (MPS I): Insights from the International MPS I Registry

MPS I: Early diagnosis, bone disease and treatment, where are we now?

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