Mis-splicing of the GALNS gene resulting from deep intronic mutations as a cause of Morquio a disease
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 a...
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BMC
2018-10-01
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| Series: | BMC Medical Genetics |
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| Online Access: | http://link.springer.com/article/10.1186/s12881-018-0694-6 |
| _version_ | 1819181825106378752 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Anna Caciotti |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T22:36:23Z |
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| institution | Directory Open Access Journal |
| issn | 1471-2350 |
| language | English |
| last_indexed | 2024-12-22T22:36:23Z |
| publishDate | 2018-10-01 |
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| series | BMC Medical Genetics |
| spelling | doaj.art-dc37d65579c440fe8a8fdf055c4116222022-12-21T18:10:17ZengBMCBMC Medical Genetics1471-23502018-10-011911910.1186/s12881-018-0694-6Mis-splicing of the GALNS gene resulting from deep intronic mutations as a cause of Morquio a diseaseAnna Caciotti0Rodolfo Tonin1Matthew Mort2David N. Cooper3Serena Gasperini4Miriam Rigoldi5Rossella Parini6Federica Deodato7Roberta Taurisano8Michelina Sibilio9Giancarlo Parenti10Renzo Guerrini11Amelia Morrone12Molecular and Cell Biology Laboratory of Neurometabolic Diseases, Paediatric Neurology Unit and Laboratories, Neuroscience Department, Meyer Children’s HospitalMolecular and Cell Biology Laboratory of Neurometabolic Diseases, Paediatric Neurology Unit and Laboratories, Neuroscience Department, Meyer Children’s HospitalInstitute of Medical Genetics, School of Medicine, Cardiff UniversityInstitute of Medical Genetics, School of Medicine, Cardiff UniversityMetabolic Unit, San Gerardo HospitalMetabolic Unit, San Gerardo HospitalMetabolic Unit, San Gerardo HospitalDivision of Metabolism, Bambino Gesù Children’s Hospital, IRCCSDivision of Metabolism, Bambino Gesù Children’s Hospital, IRCCSDepartment of Translational Medical Sciences, Section of Pediatrics, Federico II University of NaplesDepartment of Translational Medical Sciences, Section of Pediatrics, Federico II University of NaplesMolecular and Cell Biology Laboratory of Neurometabolic Diseases, Paediatric Neurology Unit and Laboratories, Neuroscience Department, Meyer Children’s HospitalMolecular and Cell Biology Laboratory of Neurometabolic Diseases, Paediatric Neurology Unit and Laboratories, Neuroscience Department, Meyer Children’s HospitalAbstract 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.http://link.springer.com/article/10.1186/s12881-018-0694-6GALNSMorquio a diseaseMucopolysaccharidosis IVADeep intronic mutationsmRNA defectsWhole gene sequencing |
| spellingShingle | 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 Mis-splicing of the GALNS gene resulting from deep intronic mutations as a cause of Morquio a disease BMC Medical Genetics GALNS Morquio a disease Mucopolysaccharidosis IVA Deep intronic mutations mRNA defects Whole gene sequencing |
| title | Mis-splicing of the GALNS gene resulting from deep intronic mutations as a cause of Morquio a disease |
| title_full | Mis-splicing of the GALNS gene resulting from deep intronic mutations as a cause of Morquio a disease |
| title_fullStr | Mis-splicing of the GALNS gene resulting from deep intronic mutations as a cause of Morquio a disease |
| title_full_unstemmed | Mis-splicing of the GALNS gene resulting from deep intronic mutations as a cause of Morquio a disease |
| title_short | Mis-splicing of the GALNS gene resulting from deep intronic mutations as a cause of Morquio a disease |
| title_sort | mis splicing of the galns gene resulting from deep intronic mutations as a cause of morquio a disease |
| topic | GALNS Morquio a disease Mucopolysaccharidosis IVA Deep intronic mutations mRNA defects Whole gene sequencing |
| url | http://link.springer.com/article/10.1186/s12881-018-0694-6 |
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