Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Medical Genetics
Published in: BMC Medical Genetics 1/2018

Open Access 01-12-2018 | Research article

Mis-splicing of the GALNS gene resulting from deep intronic mutations as a cause of Morquio a disease

Authors: Anna Caciotti, Rodolfo Tonin, Matthew Mort, David N. Cooper, Serena Gasperini, Miriam Rigoldi, Rossella Parini, Federica Deodato, Roberta Taurisano, Michelina Sibilio, Giancarlo Parenti, Renzo Guerrini, Amelia Morrone

Published in: BMC Medical Genetics | Issue 1/2018

Login to get access

Abstract

Background

Mucopolysaccharidosis-IVA (Morquio A disease) is a lysosomal disorder in which the abnormal accumulation of keratan sulfate and chondroitin-6-sulfate is consequent to mutations in the galactosamine-6-sulfatase (GALNS) gene. Since standard DNA sequencing analysis fails to detect about 16% of GALNS mutant alleles, gross DNA rearrangement screening and uniparental disomy evaluation are required to complete the molecular diagnosis. Despite this, the second pathogenic GALNS allele generally remains unidentified in ~ 5% of Morquio-A disease patients.

Methods

In an attempt to bridge the residual gap between clinical and molecular diagnosis, we performed an mRNA-based evaluation of three Morquio-A disease patients in whom the second mutant GALNS allele had not been identified. We also performed sequence analysis of the entire GALNS gene in two patients.

Results

Different aberrant GALNS mRNA transcripts were characterized in each patient. Analysis of these transcripts then allowed the identification, in one patient, of a disease-causing deep intronic GALNS mutation. The aberrant mRNA products identified in the other two individuals resulted in partial exon loss. Despite sequencing the entire GALNS gene region in these patients, the identity of a single underlying pathological lesion could not be unequivocally determined. We postulate that a combination of multiple variants, acting in cis, may synergise in terms of their impact on the splicing machinery.

Conclusions

We have identified GALNS variants located within deep intronic regions that have the potential to impact splicing. These findings have prompted us to incorporate mRNA analysis into our diagnostic flow procedure for the molecular analysis of Morquio A disease.
Appendix
Available only for authorised users
Literature
1.
Wood TC, Harvey K, Beck M, Burin MG, Chien YH, Church HJ, D’Almeida V, van Diggelen OP, Fietz M, Giugliani R et al: Diagnosing mucopolysaccharidosis IVA. J Inherit Metab Dis 2013, 36(2):293–307.CrossRef
2.
Nakashima Y, Tomatsu S, Hori T, Fukuda S, Sukegawa K, Kondo N, Suzuki Y, Shimozawa N, Orii T. Mucopolysaccharidosis IV a: molecular cloning of the human N-acetylgalactosamine-6-sulfatase gene (GALNS) and analysis of the 5′-flanking region. Genomics. 1994;20(1):99–104.CrossRef
3.
O’Leary NA, Wright MW, Brister JR, Ciufo S, Haddad D, McVeigh R, Rajput B, Robbertse B, Smith-White B, Ako-Adjei D, et al. Reference sequence (RefSeq) database at NCBI: current status, taxonomic expansion, and functional annotation. Nucleic Acids Res. 2016;44(D1):D733–45.CrossRef
4.
Aken BL, Achuthan P, Akanni W, Amode MR, Bernsdorff F, Bhai J, Billis K, Carvalho-Silva D, Cummins C, Clapham P, et al. Ensembl 2017. Nucleic Acids Res. 2017;45(D1):D635–42.CrossRef
5.
Tomatsu S, Fukuda S, Cooper A, Wraith JE, Ferreira P, Di Natale P, Tortora P, Fujimoto A, Kato Z, Yamada N et al: Fourteen novel mucopolysaccharidosis IVA producing mutations in GALNS gene. Hum Mutat 1997, 10(5):368–375.CrossRef
6.
Morrone A, Caciotti A, Atwood R, Davidson K, Du C, Francis-Lyon P, Harmatz P, Mealiffe M, Mooney S, Oron TR, et al. Morquio a syndrome-associated mutations: a review of alterations in the GALNS gene and a new locus-specific database. Hum Mutat. 2014;35(11):1271–9.PubMedPubMedCentral
7.
Tomatsu S, Montano AM, Nishioka T, Gutierrez MA, Pena OM, Tranda Firescu GG, Lopez P, Yamaguchi S, Noguchi A, Orii T. Mutation and polymorphism spectrum of the GALNS gene in mucopolysaccharidosis IVA (Morquio a). Hum Mutat. 2005;26(6):500–12.CrossRef
8.
Caciotti A, Tonin R, Rigoldi M, Ferri L, Catarzi S, Cavicchi C, Procopio E, Donati MA, Ficcadenti A, Fiumara A, et al. Optimizing the molecular diagnosis of GALNS: novel methods to define and characterize Morquio-a syndrome-associated mutations. Hum Mutat. 2015;36(3):357–68.CrossRef
9.
Hendriksz CJ, Harmatz P, Beck M, Jones S, Wood T, Lachman R, Gravance CG, Orii T, Tomatsu S. Review of clinical presentation and diagnosis of mucopolysaccharidosis IVA. Mol Genet Metab. 2013;110(1–2):54–64.CrossRef
10.
Tomatsu S, Averill LW, Sawamoto K, Mackenzie WG, Bober MB, Pizarro C, Goff CJ, Xie L, Orii T, Theroux M. Obstructive airway in Morquio a syndrome, the past, the present and the future. Mol Genet Metab. 2016;117(2):150–6.CrossRef
11.
Tomatsu S, Almeciga-Diaz CJ, Montano AM, Yabe H, Tanaka A, Dung VC, Giugliani R, Kubaski F, Mason RW, Yasuda E, et al. Therapies for the bone in mucopolysaccharidoses. Mol Genet Metab. 2015;114(2):94–109.CrossRef
12.
Tomatsu S, Sawamoto K, Almeciga-Diaz CJ, Shimada T, Bober MB, Chinen Y, Yabe H, Montano AM, Giugliani R, Kubaski F, et al. Impact of enzyme replacement therapy and hematopoietic stem cell transplantation in patients with Morquio a syndrome. Drug Des Devel Ther. 2015;9:1937–53.CrossRef
13.
Yabe H, Tanaka A, Chinen Y, Kato S, Sawamoto K, Yasuda E, Shintaku H, Suzuki Y, Orii T, Tomatsu S. Hematopoietic stem cell transplantation for Morquio a syndrome. Mol Genet Metab. 2016;117(2):84–94.CrossRef
14.
Hendriksz CJ, Parini R, AlSayed MD, Raiman J, Giugliani R, Mitchell JJ, Burton BK, Guelbert N, Stewart FJ, Hughes DA, et al. Impact of long-term elosulfase alfa on activities of daily living in patients with Morquio a syndrome in an open-label, multi-center, phase 3 extension study. Mol Genet Metab. 2018;123(2):127–34.CrossRef
15.
Khaliq T, Sadilek M, Scott CR, Turecek F, Gelb MH. Tandem mass spectrometry for the direct assay of lysosomal enzymes in dried blood spots: application to screening newborns for mucopolysaccharidosis IVA. Clin Chem. 2011;57(1):128–31.CrossRef
16.
Tomatsu S, Fujii T, Fukushi M, Oguma T, Shimada T, Maeda M, Kida K, Shibata Y, Futatsumori H, Montano AM, et al. Newborn screening and diagnosis of mucopolysaccharidoses. Mol Genet Metab. 2013;110(1–2):42–53.CrossRef
17.
Kubaski F, Mason RW, Nakatomi A, Shintaku H, Xie L, van Vlies NN, Church H, Giugliani R, Kobayashi H, Yamaguchi S et al: Newborn screening for mucopolysaccharidoses: a pilot study of measurement of glycosaminoglycans by tandem mass spectrometry. J Inherit Metab Dis 2017, 40(1):151–158.CrossRef
18.
Kubaski F, Osago H, Mason RW, Yamaguchi S, Kobayashi H, Tsuchiya M, Orii T, Tomatsu S. Glycosaminoglycans detection methods: applications of mass spectrometry. Mol Genet Metab. 2016.
19.
Montano AM, Tomatsu S, Brusius A, Smith M, Orii T. Growth charts for patients affected with Morquio a disease. Am J Med Genet A. 2008;146A(10):1286–95.CrossRef
20.
Whitley CB, Ridnour MD, Draper KA, Dutton CM, Neglia JP. Diagnostic test for mucopolysaccharidosis. I. Direct method for quantifying excessive urinary glycosaminoglycan excretion. Clin Chem. 1989;35(3):374–9.PubMed
21.
Piraud M, Boyer S, Mathieu M, Maire I. Diagnosis of mucopolysaccharidoses in a clinically selected population by urinary glycosaminoglycan analysis: a study of 2,000 urine samples. Clin Chim Acta. 1993;221(1–2):171–81.CrossRef
22.
van Diggelen OP, Zhao H, Kleijer WJ, Janse HC, Poorthuis BJ, van Pelt J, Kamerling JP, Galjaard H: A fluorimetric enzyme assay for the diagnosis of Morquio disease type a (MPS IV a). Clin Chim Acta 1990, 187(2):131–139.
23.
Caciotti A, Garman SC, Rivera-Colon Y, Procopio E, Catarzi S, Ferri L, Guido C, Martelli P, Parini R, Antuzzi D, et al. GM1 gangliosidosis and Morquio B disease: an update on genetic alterations and clinical findings. Biochim Biophys Acta. 2011;1812(7):782–90.CrossRef
24.
Galjaard H. Genetic metabolic diseases early diagnosis and prenatal analysis, vol. 825. Amsterdam: Elsevier/North Holland Biochemical Press; 1980.
25.
Macias-Vidal J, Gort L, Lluch M, Pineda M, Coll MJ. Nonsense-mediated mRNA decay process in nine alleles of Niemann-pick type C patients from Spain. Mol Genet Metab. 2009;97(1):60–4.CrossRef
26.
Noensie EN, Dietz HC. A strategy for disease gene identification through nonsense-mediated mRNA decay inhibition. Nat Biotechnol. 2001;19(5):434–9.CrossRef
27.
Usuki F, Yamashita A, Higuchi I, Ohnishi T, Shiraishi T, Osame M, Ohno S. Inhibition of nonsense-mediated mRNA decay rescues the phenotype in Ullrich’s disease. Ann Neurol. 2004;55(5):740–4.CrossRef
28.
Kervestin S, Jacobson A. NMD: a multifaceted response to premature translational termination. Nat Rev Mol Cell Biol. 2012;13(11):700–12.CrossRef
29.
Carraresi L, Parini R, Filoni C, Caciotti A, Sersale G, Tomatsu S, Orlando C, Zammarchi E, Guerrini R, Donati MA, et al. GALNS gene expression profiling in Morquio a patients’ fibroblasts. Clin Chim Acta. 2008;397(1–2):72–6.CrossRef
30.
Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46(3):310–5.CrossRef
31.
Catarzi S, Giunti L, Papadia F, Gabrielli O, Guerrini R, Donati MA, Genuardi M, Morrone A. Morquio a syndrome due to maternal uniparental isodisomy of the telomeric end of chromosome 16. Mol Genet Metab. 2012;105(3):438–42.CrossRef
32.
Bunge S, Kleijer WJ, Tylki-Szymanska A, Steglich C, Beck M, Tomatsu S, Fukuda S, Poorthuis BJ, Czartoryska B, Orii T, et al. Identification of 31 novel mutations in the N-acetylgalactosamine-6-sulfatase gene reveals excessive allelic heterogeneity among patients with Morquio a syndrome. Hum Mutat. 1997;10(3):223–32.CrossRef
33.
Zhang C, Li WH, Krainer AR, Zhang MQ. RNA landscape of evolution for optimal exon and intron discrimination. Proc Natl Acad Sci U S A. 2008;105(15):5797–802.CrossRef
34.
Sironi M, Menozzi G, Riva L, Cagliani R, Comi GP, Bresolin N, Giorda R, Pozzoli U. Silencer elements as possible inhibitors of pseudoexon splicing. Nucleic Acids Res. 2004;32(5):1783–91.CrossRef
35.
Wang Z, Gerstein M, Snyder M. RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet. 2009;10(1):57–63.CrossRef
Metadata
Title
Mis-splicing of the GALNS gene resulting from deep intronic mutations as a cause of Morquio a disease
Authors
Anna Caciotti
Rodolfo Tonin
Matthew Mort
David N. Cooper
Serena Gasperini
Miriam Rigoldi
Rossella Parini
Federica Deodato
Roberta Taurisano
Michelina Sibilio
Giancarlo Parenti
Renzo Guerrini
Amelia Morrone
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Medical Genetics / Issue 1/2018
Electronic ISSN: 1471-2350
DOI
https://doi.org/10.1186/s12881-018-0694-6

Other articles of this Issue 1/2018

BMC Medical Genetics 1/2018 Go to the issue

Research article

S100B polymorphisms are associated with age of onset of Parkinson’s disease

Research article

Analysis of the PvuII and XbaI polymorphisms in the estrogen receptor alpha gene in girls with central precocious puberty: a pilot study

Case report

A case of an infant suspected as IMAGE syndrome who were finally diagnosed with MIRAGE syndrome by targeted Mendelian exome sequencing

Case report

A novel non sense mutation in WDR62 causes autosomal recessive primary microcephaly: a case report

Research article

Updated carrier rates for c.35delG (GJB2) associated with hearing loss in Russia and common c.35delG haplotypes in Siberia

Research article

Altered DNA methylation in liver and adipose tissues derived from individuals with obesity and type 2 diabetes