Limits...
Mucopolysaccharidosis type I in 21 Czech and Slovak patients: mutation analysis suggests a functional importance of C-terminus of the IDUA protein.

Vazna A, Beesley C, Berna L, Stolnaja L, Myskova H, Bouckova M, Vlaskova H, Poupetova H, Zeman J, Magner M, Hlavata A, Winchester B, Hrebicek M, Dvorakova L - Am. J. Med. Genet. A (2009)

Bottom Line: One of the two haplotypes associated with the mutation p.Q70X was not found in any of the controls.Missense mutations localized predominantly in the hydrophobic core of the enzyme are associated with the severe phenotype, whereas missense mutations localized to the surface of the enzyme are usually associated with the attenuated phenotypes.Mutations in the 130 C-terminal amino acids lead to clinical manifestations, which indicates a functional importance of the C-terminus of the IDUA protein.

View Article: PubMed Central - PubMed

Affiliation: Institute of Inherited Metabolic Disorders, First Faculty of Medicine and General Teaching Hospital, Charles University in Prague, Prague, Czech Republic.

ABSTRACT
Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder that is caused by a deficiency of the enzyme alpha-L-iduronidase (IDUA). Of the 21 Czech and Slovak patients who have been diagnosed with MPS I in the last 30 years, 16 have a severe clinical presentation (Hurler syndrome), 2 less severe manifestations (Scheie syndrome), and 3 an intermediate severity (Hurler/Scheie phenotype). Mutation analysis was performed in 20 MPS I patients and 39 mutant alleles were identified. There was a high prevalence of the mutations p.W402X (12 alleles) and p.Q70X (7 alleles) in this cohort. Four of the 13 different mutations were novel: p.V620F (3 alleles), p.W626X (1 allele), c.1727 + 2T > G (1 allele) and c.1918_1927del (2 alleles). The pathogenicity of the novel mutations was verified by transient expression studies in Chinese hamster ovary cells. Seven haplotypes were observed in the patient alleles using 13 intragenic polymorphisms. One of the two haplotypes associated with the mutation p.Q70X was not found in any of the controls. Haplotype analysis showed, that mutations p.Q70X, p.V620F, and p.D315Y probably have more than one ancestor. Missense mutations localized predominantly in the hydrophobic core of the enzyme are associated with the severe phenotype, whereas missense mutations localized to the surface of the enzyme are usually associated with the attenuated phenotypes. Mutations in the 130 C-terminal amino acids lead to clinical manifestations, which indicates a functional importance of the C-terminus of the IDUA protein.

Show MeSH

Related in: MedlinePlus

Multiple alignment of proteins homologous to residues 523–653 of the human IDUA protein. The C-terminus of the human IDUA, which does not have a counterpart in many of the proteins from the glycohydrolase family 39, is conserved among multiple species. The residues affected by mutations in MPS I are shown by the arrows. The numbering of residues corresponds to human IDUA. Accession numbers of the sequences used in the alignment: Homo sapiens: NP_000194.2, Canis familiaris: Q01634, Bos taurus: XP_877410.2, Mus musculus: NP_032351.1, Tetraodon nigroviridis: CAG12584.1, Gallus gallus: NP_001026604.1, Danio rerio: CAM46905.1, Xenopus laevis: AAH77919.1, Strongylocentrotus purpuratus: XP_796813.2, Anopheles gambiae: XP_314521.3, Aedes aegypti: EAT44203.1, Drosophila pseudoobscura: XP_001356788.1, Drosophila melanogaster: NP_609489.1. [Color figure can be viewed in the online issue, which is available at http://www.interscience.wiley.com.]
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3526155&req=5

fig01: Multiple alignment of proteins homologous to residues 523–653 of the human IDUA protein. The C-terminus of the human IDUA, which does not have a counterpart in many of the proteins from the glycohydrolase family 39, is conserved among multiple species. The residues affected by mutations in MPS I are shown by the arrows. The numbering of residues corresponds to human IDUA. Accession numbers of the sequences used in the alignment: Homo sapiens: NP_000194.2, Canis familiaris: Q01634, Bos taurus: XP_877410.2, Mus musculus: NP_032351.1, Tetraodon nigroviridis: CAG12584.1, Gallus gallus: NP_001026604.1, Danio rerio: CAM46905.1, Xenopus laevis: AAH77919.1, Strongylocentrotus purpuratus: XP_796813.2, Anopheles gambiae: XP_314521.3, Aedes aegypti: EAT44203.1, Drosophila pseudoobscura: XP_001356788.1, Drosophila melanogaster: NP_609489.1. [Color figure can be viewed in the online issue, which is available at http://www.interscience.wiley.com.]

Mentions: Residues 523–653 of the human IDUA sequence were submitted to a protein BLAST search (http://www.ncbi.nlm.nih.gov/BLAST/) and sequences of proteins with significant homology were retrieved from the databases and aligned using ClustalW. Multiple alignment was visualized using Jalview (Fig. .1) [Clamp et al., 2004]. The positions of missense mutations in the predicted 3D structure of IDUA were examined using UCSF Chimera http://www.cgl.ucsf.edu/chimera [Pettersen et al., 2004], which was also used for the preparation of Figure 2.


Mucopolysaccharidosis type I in 21 Czech and Slovak patients: mutation analysis suggests a functional importance of C-terminus of the IDUA protein.

Vazna A, Beesley C, Berna L, Stolnaja L, Myskova H, Bouckova M, Vlaskova H, Poupetova H, Zeman J, Magner M, Hlavata A, Winchester B, Hrebicek M, Dvorakova L - Am. J. Med. Genet. A (2009)

Multiple alignment of proteins homologous to residues 523–653 of the human IDUA protein. The C-terminus of the human IDUA, which does not have a counterpart in many of the proteins from the glycohydrolase family 39, is conserved among multiple species. The residues affected by mutations in MPS I are shown by the arrows. The numbering of residues corresponds to human IDUA. Accession numbers of the sequences used in the alignment: Homo sapiens: NP_000194.2, Canis familiaris: Q01634, Bos taurus: XP_877410.2, Mus musculus: NP_032351.1, Tetraodon nigroviridis: CAG12584.1, Gallus gallus: NP_001026604.1, Danio rerio: CAM46905.1, Xenopus laevis: AAH77919.1, Strongylocentrotus purpuratus: XP_796813.2, Anopheles gambiae: XP_314521.3, Aedes aegypti: EAT44203.1, Drosophila pseudoobscura: XP_001356788.1, Drosophila melanogaster: NP_609489.1. [Color figure can be viewed in the online issue, which is available at http://www.interscience.wiley.com.]
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3526155&req=5

fig01: Multiple alignment of proteins homologous to residues 523–653 of the human IDUA protein. The C-terminus of the human IDUA, which does not have a counterpart in many of the proteins from the glycohydrolase family 39, is conserved among multiple species. The residues affected by mutations in MPS I are shown by the arrows. The numbering of residues corresponds to human IDUA. Accession numbers of the sequences used in the alignment: Homo sapiens: NP_000194.2, Canis familiaris: Q01634, Bos taurus: XP_877410.2, Mus musculus: NP_032351.1, Tetraodon nigroviridis: CAG12584.1, Gallus gallus: NP_001026604.1, Danio rerio: CAM46905.1, Xenopus laevis: AAH77919.1, Strongylocentrotus purpuratus: XP_796813.2, Anopheles gambiae: XP_314521.3, Aedes aegypti: EAT44203.1, Drosophila pseudoobscura: XP_001356788.1, Drosophila melanogaster: NP_609489.1. [Color figure can be viewed in the online issue, which is available at http://www.interscience.wiley.com.]
Mentions: Residues 523–653 of the human IDUA sequence were submitted to a protein BLAST search (http://www.ncbi.nlm.nih.gov/BLAST/) and sequences of proteins with significant homology were retrieved from the databases and aligned using ClustalW. Multiple alignment was visualized using Jalview (Fig. .1) [Clamp et al., 2004]. The positions of missense mutations in the predicted 3D structure of IDUA were examined using UCSF Chimera http://www.cgl.ucsf.edu/chimera [Pettersen et al., 2004], which was also used for the preparation of Figure 2.

Bottom Line: One of the two haplotypes associated with the mutation p.Q70X was not found in any of the controls.Missense mutations localized predominantly in the hydrophobic core of the enzyme are associated with the severe phenotype, whereas missense mutations localized to the surface of the enzyme are usually associated with the attenuated phenotypes.Mutations in the 130 C-terminal amino acids lead to clinical manifestations, which indicates a functional importance of the C-terminus of the IDUA protein.

View Article: PubMed Central - PubMed

Affiliation: Institute of Inherited Metabolic Disorders, First Faculty of Medicine and General Teaching Hospital, Charles University in Prague, Prague, Czech Republic.

ABSTRACT
Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder that is caused by a deficiency of the enzyme alpha-L-iduronidase (IDUA). Of the 21 Czech and Slovak patients who have been diagnosed with MPS I in the last 30 years, 16 have a severe clinical presentation (Hurler syndrome), 2 less severe manifestations (Scheie syndrome), and 3 an intermediate severity (Hurler/Scheie phenotype). Mutation analysis was performed in 20 MPS I patients and 39 mutant alleles were identified. There was a high prevalence of the mutations p.W402X (12 alleles) and p.Q70X (7 alleles) in this cohort. Four of the 13 different mutations were novel: p.V620F (3 alleles), p.W626X (1 allele), c.1727 + 2T > G (1 allele) and c.1918_1927del (2 alleles). The pathogenicity of the novel mutations was verified by transient expression studies in Chinese hamster ovary cells. Seven haplotypes were observed in the patient alleles using 13 intragenic polymorphisms. One of the two haplotypes associated with the mutation p.Q70X was not found in any of the controls. Haplotype analysis showed, that mutations p.Q70X, p.V620F, and p.D315Y probably have more than one ancestor. Missense mutations localized predominantly in the hydrophobic core of the enzyme are associated with the severe phenotype, whereas missense mutations localized to the surface of the enzyme are usually associated with the attenuated phenotypes. Mutations in the 130 C-terminal amino acids lead to clinical manifestations, which indicates a functional importance of the C-terminus of the IDUA protein.

Show MeSH
Related in: MedlinePlus