Mucopolysaccharidosis IVA: characterization of a common mutation found in Finnish patients with attenuated phenotype

Montaño, Adriana M.; Kaitila, Ilkka; Sukegawa, Kazuko; Tomatsu, Shunji; Kato, Zenichiro; Nakamura, Haruki; Fukuda, Seiji; Orii, Tadao; Kondo, Naomi

doi:10.1007/s00439-003-0959-8

Cited by 31 publications

(24 citation statements)

References 38 publications

(27 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The remaining 46% of mutations occur less than 3 times in the total population, suggesting that molecular heterogeneity in GALNS mutations is marked. The most prevalent c.1156C>T transitional mutation at CpG dinucleotide (p.R386C) was found in 9% of patients from various ethnic groups origin (9;10;32;98;99). …”

Section: Laboratory Diagnoses Of Mps Ivamentioning

confidence: 99%

See 1 more Smart Citation

Review of clinical presentation and diagnosis of mucopolysaccharidosis IVA

Hendriksz

Harmatz²,

Beck

et al. 2013

Molecular Genetics and Metabolism

150

176

View full text Add to dashboard Cite

Mucopolysaccharidosis type IVA (MPS IVA) was described in 1929 by Luis Morquio from Uruguay and James Brailsford from England, and was later found as an autosomal recessive lysosomal storage disease. MPS IVA is caused by mutations in the gene encoding the enzyme, N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Reduced GALNS activity results in impaired catabolism of two glycosaminoglycans (GAGs), chondroitin-6-sulfate (C6S) and keratan sulfate (KS). Clinical presentations of MPS IVA reflect a spectrum of progression from a severe ”classical” phenotype to a mild “attenuated” phenotype. More than 180 different mutations have been identified in the GALNS gene, which likely explains the phenotypic heterogeneity of the disorder. Accumulation of C6S and KS manifests predominantly as short stature and skeletal dysplasia (dysostosis multiplex), including atlantoaxial instability and cervical cord compression. However, abnormalities in the visual, auditory, cardiovascular, and respiratory systems can also affect individuals with MPS IVA. Diagnosis is typically based on clinical examination, skeletal radiographs, urinary GAG, and enzymatic activity of GALNS in blood cells or fibroblasts. Deficiency of GALNS activity is a common assessment for the laboratory diagnosis of MPS IVA; however, with recently increased availability, gene sequencing for MPS IVA is often used to confirm enzyme results. As multiple clinical presentations are observed, diagnosis of MPS IVA may require multi-system considerations. This review provides a history of defining MPS IVA and how the understanding of the disease manifestations has changed over time. A summary of the accumulated knowledge is presented, including information from the International Morquio Registry. The classical phenotype is contrasted with attenuated cases, which are now being recognized and diagnosed more frequently. Laboratory based diagnoses of MPS IVA are also discussed.

show abstract

Section: Laboratory Diagnoses Of Mps Ivamentioning

confidence: 99%

“…Clinical presentations of severely affected patients have been reported as severe (29;30), or classical (28–30) phenotypes. Less severe forms of MPS IVA have been reported as mild (30;31) or attenuated (7;9) phenotypes. As well, an intermediate subtype of MPS IVA has been proposed (29;30;32).…”

Section: Introductionmentioning

confidence: 99%

Review of clinical presentation and diagnosis of mucopolysaccharidosis IVA

Hendriksz

Harmatz²,

Beck

et al. 2013

Molecular Genetics and Metabolism

150

176

View full text Add to dashboard Cite

show abstract

“…To date, about 150 different mutations have been identified. This heterogeneity in GALNS gene mutations accounts for extensive clinical variability of MPS IVA (Fukuda et al 1992;Hori et al 1995;Kato et al 1997;Montaño et al 2003;Ogawa et al 1995;Terzioglu et al 2002;Tomatsu et al 2005a;Yamada et al 1998). Genotype-phenotype correlation exists for some of these mutations.…”

Section: Introductionmentioning

confidence: 99%

International Morquio A Registry: Clinical manifestation and natural course of Morquio A disease

Montaño¹,

Tomatsu²,

Gottesman³

et al. 2007

J of Inher Metab Disea

305

428

View full text Add to dashboard Cite

Mucopolysaccharidosis IVA (MPS IVA; Morquio A disease) is a lysosomal storage disorder caused by deficiency of N-acetylgalactosamine-6-sulfate sulfatase. The natural history of this disease is incompletely understood. To study which variables influence the clinical outcome, we conducted a study in which MPS IVA patients were asked to fill out a questionnaire with inquiries regarding family history, diagnosis, signs and symptoms, height, weight, surgical history, physical activity, and general complaints. A total of 326 patients (172 male, 154 female) from 42 countries enrolled in the Morquio A Registry programme. The mean age of patients enrolled was 14.9 years for males and 19.1 years for females, with a wide range of 1-73 years. Sixty-four per cent of the patients were under 18 years. Initial symptoms were recognized between 1 and 3 years of age (mean age 2.1 years) and mean age at diagnosis for the patients was 4.7 years. A progressive skeletal dysplasia was commonly observed among the MPS IVA patients. Fifty per cent of patients underwent surgical operations to improve their quality of life. The most frequent surgical sites include neck (51%), ear (33%), leg (26%) and hip (25%). The birth length for affected males and females was 52.2 +/- 4.7 cm and 52.2 +/- 4.5 cm, respectively. The final adult height for affected males and females was 122.5 +/- 22.5 cm and 116.5 +/- 20.5 cm, respectively. The results of this study provide a reference for assessment of efficacy for studies of novel therapies.

show abstract

“…To elucidate genotype-phenotype correlation, some of the mutations identified were analysed by in vitro transient expression using the MPS IVA fibroblasts. The mutants found in the severe phenotype had under 1% of normal cDNA GALNS activity, while most mutants found in the attenuated phenotype had a higher residual activity (2.2-17.4% of wild-type GALNS activity), indicating a good correlation between the transient expression level and the clinical phenotype (Fukuda et al 1992;Kato et al 1997;Montañ o et al 2003;Ogawa et al 1995;Sukegawa et al 2000;Tomatsu et al 1995aTomatsu et al ,b, 1997Yamada et al 1998).…”

mentioning

confidence: 98%

“…The GALNS gene has been mapped to chromosome 16q24.3 (Baker et al 1993;Masuno et al 1993). Up to now, around 150 different mutations have been found in more than 200 patients of various ethnic backgrounds showing extensive allelic heterogeneity (Bunge et al 1997;Fukuda et al 1996Fukuda et al , 1997Kato et al 1997;Montañ o et al 2003;Tomatsu et al 1995aTomatsu et al ,b, 1996Tomatsu et al , 1997Tomatsu et al , 2004aTomatsu et al ,b,c, 2005Yamada et al 1998). To elucidate genotype-phenotype correlation, some of the mutations identified were analysed by in vitro transient expression using the MPS IVA fibroblasts.…”

mentioning

confidence: 99%

Effect of ‘attenuated’ mutations in mucopolysaccharidosis IVA on molecular phenotypes of N‐acetylgalactosamine‐6‐sulfate sulfatase

Montaño¹,

Sukegawa²,

Kato³

et al. 2007

J of Inher Metab Disea

View full text Add to dashboard Cite

Mucopolysaccharidosis IVA is an autosomal recessive disease caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Mutation screening of the GALNS gene was performed for seven MPS IVA patients with attenuated phenotypes from three unrelated families. Four of 5 missense mutations identified in this study (p.F167V, p.R253W, p.R380S, p.P484S) and two reported (p.F97V, p.N204K), associated with attenuated phenotypes, were characterized using in vitro stable expression experiments, enzyme kinetic study, protein processing and structural analysis. The stably expressed mutant enzymes defining the attenuated phenotype exhibited a considerable residual activity (1.2-36.7% of the wild-type GALNS activity) except for p.R380S. Enzyme kinetic studies showed that p.F97V, p.F167V and p.N204K have lower affinity to the substrate compared with other mutants. The p.F97V enzyme was the most thermolabile at 55 degrees C. Immunoblot analyses indicated a rapid degradation and/or an insufficiency in processing in the mutant proteins. Tertiary structure analysis revealed that although there was a tendency for 'attenuated' mutant residues to be located on the surface of GALNS, they have a different effect on the protein including modification of the hydrophobic core and salt-bridge formation and different potential energy. This study demonstrates that 'attenuated' mutant enzymes are heterogeneous in molecular phenotypes, including biochemical properties and tertiary structure.

show abstract

Mucopolysaccharidosis IVA: characterization of a common mutation found in Finnish patients with attenuated phenotype

Cited by 31 publications

References 38 publications

Review of clinical presentation and diagnosis of mucopolysaccharidosis IVA

Review of clinical presentation and diagnosis of mucopolysaccharidosis IVA

International Morquio A Registry: Clinical manifestation and natural course of Morquio A disease

Effect of ‘attenuated’ mutations in mucopolysaccharidosis IVA on molecular phenotypes of N‐acetylgalactosamine‐6‐sulfate sulfatase

Contact Info

Product

Resources

About