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. 2014 Jun;112(2):160-70.
doi: 10.1016/j.ymgme.2014.03.004. Epub 2014 Mar 20.

Molecular testing of 163 patients with Morquio A (Mucopolysaccharidosis IVA) identifies 39 novel GALNS mutations

A Morrone  1 , K L Tylee  2 , M Al-Sayed  3 , A C Brusius-Facchin  4 , A Caciotti  5 , H J Church  2 , M J Coll  6 , K Davidson  7 , M J Fietz  8 , L Gort  6 , M Hegde  9 , F Kubaski  4 , L Lacerda  10 , F Laranjeira  10 , S Leistner-Segal  4 , S Mooney  11 , S Pajares  6 , L Pollard  12 , I Ribeiro  10 , R Y Wang  13 , N Miller  14
Affiliations

Molecular testing of 163 patients with Morquio A (Mucopolysaccharidosis IVA) identifies 39 novel GALNS mutations

A Morrone et al. Mol Genet Metab. 2014 Jun.

Erratum in

  • Mol Genet Metab. 2014 Nov;113(3):237

Abstract

Morquio A (Mucopolysaccharidosis IVA; MPS IVA) is an autosomal recessive lysosomal storage disorder caused by partial or total deficiency of the enzyme galactosamine-6-sulfate sulfatase (GALNS; also known as N-acetylgalactosamine-6-sulfate sulfatase) encoded by the GALNS gene. Patients who inherit two mutated GALNS gene alleles have a decreased ability to degrade the glycosaminoglycans (GAGs) keratan sulfate and chondroitin 6-sulfate, thereby causing GAG accumulation within lysosomes and consequently pleiotropic disease. GALNS mutations occur throughout the gene and many mutations are identified only in single patients or families, causing difficulties both in mutation detection and interpretation. In this study, molecular analysis of 163 patients with Morquio A identified 99 unique mutations in the GALNS gene believed to negatively impact GALNS protein function, of which 39 are previously unpublished, together with 26 single-nucleotide polymorphisms. Recommendations for the molecular testing of patients, clear reporting of sequence findings, and interpretation of sequencing data are provided.

Keywords: GALNS; Lysosomal storage disorder; MPS IVA; Morquio A; Mucopolysaccharidosis type IVA; Mutation.

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Conflict of interest statement

Conflicts of Interest:

Dr Fietz has received travel support and honoraria from BioMarin Pharmaceutical. Drs Church, Morrone, and Tylee have received consultant fees and limited travel support from BioMarin Pharmaceutical and provide a diagnostic service for MPS for samples from Turkey that is funded by BioMarin. Dr Pollard is a paid employee of the Greenwood Genetic Center, which has contracts with BioMarin. Dr Wang holds a financial interest in BioMarin. Dr Mooney serves as a consultant for BioMarin Pharmaceutical. Mrs Davidson and Dr Miller are employees of BioMarin. Drs Al-Sayed, Brusius-Facchin, Caciotti, Coll, Gort, Kubaski, Lacerda, Laranjeira, Leistner-Segal, Pajares, and Riberio declare no potential conflicts of interest.

Figures

Figure 1
Figure 1. Location of 39 novel mutations detected in the GALNS gene
Exons are depicted as boxes and labeled with roman numerals. Novel alleles are color coded by their classification per Table 1.
Figure 2
Figure 2. Location of novel Morquio A missense mutations mapped on the protein structure of the human GALNS protein
Novel missense mutations identified in this study are mapped on the human GALNS protein structure (pdb:4FDI). Mutations identified were mapped to the structure and visualized using UCSF Chimera (http://www.cgl.ucsf.edu/chimera). The protein chain is represented as a ribbon showing beta sheets as light purple and alpha helices as light red, surrounded by a transparent solvent excluded surface. Mutation positions are represented as spheres for the wild type side chains. Note that position 16 is in the N-terminal disordered region. Mutations colored in orange are predicted to affect GALNS active site primary residues; all others are colored in blue.
Figure 3
Figure 3. Potential complexity of patient genotypes
For three example initial genotyping results (apparently heterozygous, apparently homozygous, and apparently a compound heterozygote), illustrates how parental genotyping results can confirm the initial genotype or reveal unanticipated complexity.
See this image and copyright information in PMC

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