Mutation Database for N-acetylgalactosamine-6-sulfatase, GALNS

Mutations in the human GALNS gene can lead to Mucopolysaccharidosis IVA (MPS IVA) also known as Morquio A disease OMIM: 253000 (Tomatsu et al. 1991; Hamosh et al. 2005). In 1929, James Brailsford in England and Dr. Luis Morquio in Uruguay were the first to describe the symptoms of patients with MPS IVA (Brailsford 1929; Morquio 1929). This rare disease is autosomal recessive and is caused by a deficiency in N-acetylgalactosamine-6-sulfate sulfatase enzyme (Matalon et al. 1974; Hendriksz et al. 2013). This deficiency leads to accumulation of uncatabolized keratin sulfate and chrondroitin-6-sulfate in the lysosomes of cells (Matalon et al. 1974; Singh et al. 1976; Rivera-Colon et al. 2012).

MPS IVA is a lysosomal storage disorder that is caused by a complex heterozygosity or homozygosity of over 180 pathogenic GALNS gene mutations (Hendriksz et al. 2013). This complex heterozygosity results in a range of symptoms and a variable degree of phenotypic severity for MPS IVA patients (Tomatsu et al. 2005). Patients with the severe MPS IVA phenotype can exhibit such symptoms as growth retardation, and skeletal dysplasia among others and often do not live past their twenties (Montaño et al. 2007b; Montaño et al. 2008; Algahim and Almassi 2013; Hendriksz et al. 2013). On the other hand, patients with the mild/attenuated phenotype may live fifty to sixty years with mild bone involvement (Montaño et al. 2003; Montaño et al. 2007a; Algahim and Almassi 2013; Hendriksz et al. 2013).

The GALNS mutation database utilizes sequence accessions from the National Center for Biotechnology (www.ncbi.nlm.nih.gov). The human GALNS gene occurs at the chromosomal location 16q24.3 (88880142..88923374) and has 14 exons (Baker et al. 1993; Masuno et al. 1993; Hamosh et al. 2005). Mutations at the nucleotide level are represented using the cDNA sequence NM_000512.14 (2,380 bp) as a reference. At the protein level, changes in amino acids are documented utilizing the reference sequence NP_000503.1 (522 aa). The chromosomal reference sequence used was NC_000016.9.

The results of two mutation prediction software tools, Mutpred and Polyphen-2, are displayed to aid assessment as to whether an amino acid substitution is potentially deleterious. These predictions cannot be used for clinical decisions or diagnosis. Mutpred is a computational model that analyzes differences in mutant and wild type sequences. A MutPred score cutoff of 0.5 was used to classify variations as ‘predicted non-pathogenic’ or ‘predicted pathogenic’. The probability of an amino acid substitution causing disease is calculated by modeling the mutations effect on the function and structure of a protein (Li et al. 2009). Polyphen-2 is another computational model for disease prediction of missense mutations. Predictions are based on sequence and protein structure analysis (Adzhubei et al. 2010).

Much of the GALNS database was sourced from the literature and publicly available databases. It contains pathogenic and non-pathogenic mutations. If a particular mutation is listed in dbSNP (www.ncbi.nlm.nih.gov/SNP), SwissProt (www.uniprot.org) or Cosmic (cancer.sanger.ac.uk/cosmic), an external link is provided for the entry. Mutations with associated journal articles with PubMed ID’s are displayed under references. We provide a JMOL protein structure viewer (Jmol: an open-source Java viewer for chemical structures in 3D. http://www.jmol.org/, accessed February 2014) for visualization of each mutation.

Nucleotide and amino acid sequence variations conform to the Human Genome Variation Society guidelines for nomenclature (www.hgvs.org). Nucleotide mutations are referenced using the cDNA reference sequence. Starting positions for cDNA sequence mutations are calculated from the first nucleotide of the start codon. Intronic mutations are calculated + or - from the first or last nucleotide of an exon within the cDNA reference sequence. Stop codons are noted as an asterisk.

Phenotypic classifications that are added online to the database should follow the recommendations in the Emory Genetics Laboratory classification definitions (http://genetics.emory.edu/egl/emvclass/EGLClassificationDefinitions.php). Phenotypes are described as either being Pathogenic, Likely Pathogenic, Benign variant, Likely benign variant or Variant of unknown clinical significance (VOUS). If data sourced from a journal article described a phenotype as severe, attenuated or mild this information was added under curator notes.

No user registration is required to access the database. Users can download a copy of the GALNS database in .csv format. Researchers are encouraged to add new GALNS mutations to the database via the submission option. Submitted mutations won’t appear in the database until they have been curated.

All submissions to the GALNS database will be curated moving forward by our curation team. New mutations that are submitted will not appear in the database until they have been evaluated by the curator. To further the completeness of the GALNS database, researchers are encouraged to report any discrepancies they find or suggest additional information for existing database entries via the email address available on the website. If you would like to be considered as a future curator please contact us.



DISCLAIMER

This site is offered “As Is” with no guarantee of completeness or accuracy of the information provided. These mutations are meant to be used for basic research. Medical professionals, researchers, clinicians and others must use all available diagnostic methods to assess a patient’s medical condition. Do not use any of the data in this site to make clinical decisions. The Buck Institute for research on aging and its staff, galns.mutdb.org curators and those who submit mutations to the database are not responsible for errors or omissions on this website or damages that you might incur. You assume all responsibility and risk for using this site. None of the sequence data in this site came from the Buck Institute for research on aging. The annotations may be freely downloaded and used for non-commercial use as long as galns.mutdb.org is properly cited. The underlying mutation data is derived from other sources such as dbSNP, Swiss-Prot, Cosmic, curators, user submittals and journal articles. Any use of the underlying mutation data may be subject to restrictions. Please inquire with the source data provider (linked on every mutation annotation page) for more information.



REFERENCES

Adzhubei I a, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR. 2010. A method and server for predicting damaging missense mutations. Nat. Methods 7: 248-9.

Algahim MF, Almassi GH. 2013. Current and emerging management options for patients with Morquio A syndrome. Ther. Clin. Risk Manag. 9: 45-53.

Baker E, Guo X, Orsborn AM, Sutherland GR, Callen DF, Hopwood JJ, Morrist CP. 1993. The Morquio A Syndrome (Mucopolysaccharidosis IVA) Gene Maps to 1 6q24.3. Am. J. Hum. Genet. 52: 96-98.

Brailsford JF. 1929. Chondro-osteo-dystrophy. Roentgenographic and clinical features of a child with dislocation of vertebrae. Am. J. Surg. 7: 404-410.

Hamosh A, Scott AF, Amberger JS, Bocchini C a, McKusick V a. 2005. Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders. Nucleic Acids Res. 33: D514-7.

Hendriksz CJ, Harmatz P, Beck M, Jones S, Wood T, Lachman R, Gravance CG, Orii T, Tomatsu S. 2013. Review of clinical presentation and diagnosis of mucopolysaccharidosis IVA. Mol. Genet. Metab. 110: 54-64.

Li B, Krishnan VG, Mort ME, Xin F, Kamati KK, Cooper DN, Mooney SD, Radivojac P. 2009. Automated inference of molecular mechanisms of disease from amino acid substitutions. Bioinformatics 25: 2744-50.

Masuno M, Tomatsu S, Nakashima Y, Hori T, Fukuda S, Masue M, Sukegawa K, Orii T. 1993. Mucopolysaccharidosis IVA: assignment of the human N-acetylgalactosamine-6- sulfate sulfatase (GALNS) gene to chromosome 16q24. Genomics 16: 777-78.

Matalon R, Arbogast B, Justice P, Brandt IK, Dorfman A. 1974. MORQUIO’S SYNDROME: DEFICIENCY OF A CHONDROITIN SULFATE N-ACETYLHEXOSAMINE SULFATE SULFATASE. Biochem. Biophsical Res. Commun. 61: 759-765.

Montaño a M, Sukegawa K, Kato Z, Carrozzo R, Natale P Di, Christensen E, Orii KO, Orii T, Kondo N, Tomatsu S. 2007a. Effect of “attenuated” mutations in mucopolysaccharidosis IVA on molecular phenotypes of N-acetylgalactosamine-6-sulfate sulfatase. J. Inherit. Metab. Dis. 30: 758-67.

Montaño a M, Tomatsu S, Gottesman GS, Smith M, Orii T. 2007b. International Morquio A Registry: clinical manifestation and natural course of Morquio A disease. J. Inherit. Metab. Dis. 30: 165-74.

Montaño a M, Kaitila I, Sukegawa K, Tomatsu S, Kato Z, Nakamura H, Fukuda S, Orii T, Kondo N. 2003. Mucopolysaccharidosis IVA: characterization of a common mutation found in Finnish patients with attenuated phenotype. Hum. Genet. 113: 162-9.

Montaño a M, Tomatsu S, Brusius A, Smith M, Orii T. 2008. Growth charts for patients affected with Morquio A disease. Am. J. Med. Genet. A 146A: 1286-95.

Morquio L. 1929. Sur une forme de dystrophie osseuse familiale. Arch. Med. des infants 32: 129-135.

Rivera-Colon Y, Schutsky EK, Kita AZ, Garman SC. 2012. The structure of human GALNS reveals the molecular basis for mucopolysaccharidosis IV A. J. Mol. Biol. 423: 736-51.

Singh J, Ferrante N Di, Niebes P. 1976. N-acetylgalactosamine-6-sulfate sulfatase in man. Absence of the enzyme in Morquio disease. 57: 1036-1040.

Tomatsu S, Fukuda S, Masue M, Sukegawa K, Fukao T, Yamagishi A, Hori T, Iwata H, Ogawa T, Nakashima Y, Hanyu Y, Hashimoto T, et al. 1991. Morquio disease: isolation, characterization and expression of full-length cDNA for human N-acetylgalactosamine-6-sulfate sulfatase. Biochem. Biophsical Res. Commun. 181: 677-683.

Tomatsu S, Montaño a M, Nishioka T, Gutierrez M a, Pe¤a OM, Tranda Firescu GG, Lopez P, Yamaguchi S, Noguchi A, Orii T. 2005. Mutation and polymorphism spectrum of the GALNS gene in mucopolysaccharidosis IVA (Morquio A). Hum. Mutat. 26:500-12.