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

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 produce protein with 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99 unique mutations in the GALNS gene believed to negatively impact GALNS protein function, of which 39 are previously unpublished, together with 26 single-nucleotide polymorphisms.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.

Optimizing the Molecular Diagnosis of GALNS: Novel Methods to Define and Characterize Morquio-A Syndrome-Associated Mutations

“…The critical issues for the differential diagnosis of MPS IVA have been previously underlined [Wood et al., ; Morrone et al., b]. We found diagnostic key elements previously identified and data reported from the International Morquio Registry [Montano et al., ] and MorCAP program [Harmatz et al., ] useful for categorizing our cohort.…”

Molecular diagnosis of patients affected by mucopolysaccharidosis: a multicenter study

“…(Gly116Ser)–[61]Likely pathogenicc.347G>Tp. (Gly116Val)–[40]Likely pathogenicc.463G>Ap. (Gly155Arg)rs398123438; ClinVar ID:93178[12]Likely pathogenicc.868G>Ap.…”

“…(Cys507Arg)–[14]Likely pathogenicc.1520G>Tp. (Cys507Phe)ClinVar ID:93169[40]Not enough evidenceNC_000016.9: g.88836836_88899132del62296––[14]Likely pathogenicc.1002+307G>C––[15]Not enough evidence GLB1 (NM_000404.3; NP_000395.2)Single nucleotide variationMissense variant–Novel; Morrone A et al in publication–c.817_818delinsCTp. (Trp273Leu)–[44]Likely pathogenicc.1480-2A>G–rs587776526; ClinVar ID: 946[39]Pathogenic ARSB (NM_000046.4; NP_000037.2)c.245T>Cp.…”

A homozygous founder missense variant in arylsulfatase G abolishes its enzymatic activity causing atypical Usher syndrome in humans

“…Of note, mutations in the corresponding aspartate residue in N-sulfoglucosamine sulfohydrolase (encoded by SGSH) and Nacetylgalactosamine-6-sulfatase (encoded by GALNS) cause loss-of-function alleles resulting in different forms of mucopolysaccharidosis (MPS type IIIA and IVA, respectively). 20,21 Arylsulfatase G was identified in 2002 as a novel sulfatase gene 18 and has been further characterized biochemically as a lysosomal sulfatase. 15 As mentioned above, aspartate-45 is part of the ARSG active site, where it coordinates a calcium ion next to the catalytic formylglycine (FGly) residue that is essential for all human sulfatases.…”