Morquio A syndrome-associated mutations: a review of alterations in the GALNS gene and a new locus-specific database

Abstract

Morquio A syndrome (mucopolysaccharidosis IVA) is an autosomal recessive disorder that results from deficient activity of the enzyme N-acetylgalactosamine-6-sulfatase (GALNS) due to alterations in the GALNS gene, which causes major skeletal and connective tissue abnormalities and effects on multiple organ systems. The GALNS alterations associated with Morquio A are numerous and heterogeneous, and new alterations are continuously identified. To aid detection and interpretation of GALNS alterations, from previously published research, we provide a comprehensive and up-to-date listing of 277 unique GALNS alterations associated with Morquio A identified from 1,091 published GALNS alleles. In agreement with previous findings, most reported GALNS alterations are missense changes and even the most frequent alterations are relatively uncommon. We found that 48% of patients are assessed as homozygous for a GALNS alteration, 39% are assessed as heterozygous for two identified GALNS alterations, and in 13% of patients only one GALNS alteration is detected. We report here the creation of a locus-specific database for the GALNS gene (http://galns.mutdb.org/) that catalogs all reported alterations in GALNS to date. We highlight the challenges both in alteration detection and genotype-phenotype interpretation caused in part by the heterogeneity of GALNS alterations and provide recommendations for molecular testing of GALNS.

Keywords: GALNS; MPS IVA; Morquio A; lysosomal storage disorder; mucopolysaccharidosis type IVA.

© 2014 The Authors. **Human Mutation published by Wiley Periodicals, Inc.

Figures

Figure 1

GALNS Gene Structure: a view of most frequently reported alleles and reported large deletions/rearrangements. GALNS enzyme primary active site residues (Rivera-Colon et al., 2012) are indicated (*): p.Asp39, p.Asp40, p.Cys/dihydroxyalanine79, p.Arg83, p.Tyr108, p.Lys140, p.His142, p.His236, p.Asp288, p.Asn289, and p.Lys310.

Figure 2

Population properties of published patients with Morquio A. A: A plurality of patients with Morquio A are reported to be homozygous for a GALNS gene alteration. All Morquio A patients with GALNS gene alteration data presented as a genotype were divided into the following categories: those assessed to be homozygous for a reported GALNS gene alteration, heterozygous for two reported GALNS gene alterations, or only one mutated GALNS allele reported. B: Frequency of reported alleles in patients with Morquio A by mutation type. GALNS alleles reported from patients with Morquio A (i.e., totaling all reports of a given gene alteration; n = 1091) are categorized by alteration type; missense alterations are further divided between the three most frequently reported alterations in the GALNS gene (c.1156C>T [p.R386C; n = 55]; c.337A>T [p.I113F; n = 52]; and c.901G>T [p.G301C; n = 45]) and all other missense alterations (n = 706). C: Most GALNS gene alterations are rare. All reported GALNS alleles are categorized and graphed by how often they have been reported in patients with Morquio A. Gene alterations that have been reported only once or twice (two left columns) are divided between those gene alterations reported in a single patient or two or more patients. Two of the 87 alterations in the GALNS gene only reported once are from one instance of a GALNS allele reported from a patient with Morquio A where two missense alterations—with unknown individual association with disease—are present in cis [Morrone et al., 2014]. The most frequently reported GALNS gene alterations are listed in columns in order of reported frequency, with the top listed gene alterations the most frequently reported within that category.

Figure 3

Assessed growth phenotype severity of patients with Morquio A, by GALNS gene alteration type. All patients assessed as homozygous for a GALNS gene alteration were grouped by their assessed growth phenotype and then divided by alteration type. Assessments of “attenuated,” “slowly progressing,” or “mild” growth phenotypes were grouped with “less severe” (n = 26); assessments of “moderate” were grouped with “intermediate” (n = 6); and assessments of “rapidly progressing” and “severe” were grouped with “most severe” (n = 107). Graph labels show the numbers of each GALNS gene alteration type reported.