RNA analysis of the GALNS transcript reveals novel pathogenic mechanisms associated with Morquio syndrome A
Morquio syndrome A (Mucopolysaccharidosis IVA, MPS IVA) is an autosomal recessive lysosomal storage disorder caused by deficiency of N-acetyl-galactosamine-6-sulfatase (GALNS) which catabolizes the glycosaminoglycans (GAG), keratan sulfate and chondroitin-6-sulfate. Homozygous or compound heterozygo...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-06-01
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| Series: | Molecular Genetics and Metabolism Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214426922000350 |
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| author | Young Bae Sohn Curtis Rogers Jennifer Stallworth Jessica A. Cooley Coleman Laura Buch Erin Jozwiak Jo Ann Johnson Tim Wood Paul Harmatz Laura Pollard Raymond J. Louie |
| author_facet | Young Bae Sohn Curtis Rogers Jennifer Stallworth Jessica A. Cooley Coleman Laura Buch Erin Jozwiak Jo Ann Johnson Tim Wood Paul Harmatz Laura Pollard Raymond J. Louie |
| author_sort | Young Bae Sohn |
| collection | DOAJ |
| description | Morquio syndrome A (Mucopolysaccharidosis IVA, MPS IVA) is an autosomal recessive lysosomal storage disorder caused by deficiency of N-acetyl-galactosamine-6-sulfatase (GALNS) which catabolizes the glycosaminoglycans (GAG), keratan sulfate and chondroitin-6-sulfate. Homozygous or compound heterozygous pathogenic variants in the GALNS result in the deficiency of the enzyme and consequent GAG accumulations. DNA sequence and copy number analysis of the GALNS coding region fails to identify biallelic causative pathogenic variants in up to 15% of patients with Morquio syndrome A. RNA transcript analysis was performed to identify pathogenic alterations in two unrelated families with Morquio syndrome A in whom a single heterozygous or no pathogenic alteration was detected by standard analysis of the GALNS gene. RNA sequencing and quantitative expression analysis identified the overabundance of an aberrant GALNS transcript isoform and a reduction of the clinically relevant isoform (NM_000512.4) in the Morquio syndrome A patients from both families. The aberrant isoform (ENST00000568613.1) was produced by alternative splicing and contained intronic sequence that was likely a cryptic exon predicted to result in a reading frame shift and generation of a premature termination codon. These findings indicated that the aberrant splicing is likely the novel molecular defect in our patients. RNA transcript analysis could be useful to identify pathogenic alterations and increase the yield of molecular diagnosis in patients with Morquio syndrome A whose genetic variants are not found by standard sequencing or gene dosage analysis. |
| first_indexed | 2024-12-12T04:25:30Z |
| format | Article |
| id | doaj.art-17a846fdbc06476496d165a9c3b86ed3 |
| institution | Directory Open Access Journal |
| issn | 2214-4269 |
| language | English |
| last_indexed | 2024-12-12T04:25:30Z |
| publishDate | 2022-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Genetics and Metabolism Reports |
| spelling | doaj.art-17a846fdbc06476496d165a9c3b86ed32022-12-22T00:38:12ZengElsevierMolecular Genetics and Metabolism Reports2214-42692022-06-0131100875RNA analysis of the GALNS transcript reveals novel pathogenic mechanisms associated with Morquio syndrome AYoung Bae Sohn0Curtis Rogers1Jennifer Stallworth2Jessica A. Cooley Coleman3Laura Buch4Erin Jozwiak5Jo Ann Johnson6Tim Wood7Paul Harmatz8Laura Pollard9Raymond J. Louie10Department of Medical Genetics, Ajou University Hospital, Ajou University School of Medicine, Suwon, Republic of Korea; Corresponding author at: Department of Medical Genetics, Ajou University Hospital, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea.Greenwood Genetic Center, Greenwood, SC, USAGreenwood Genetic Center, Greenwood, SC, USAGreenwood Genetic Center, Greenwood, SC, USAGreenwood Genetic Center, Greenwood, SC, USAUCSF Benioff Children's Hospital Oakland, Oakland, CA, USAUCSF Benioff Children's Hospital Oakland, Oakland, CA, USASection of Genetics and Metabolism, University of Colorado/Children's Hospital of Colorado, Aurora, CO, USAUCSF Benioff Children's Hospital Oakland, Oakland, CA, USAGreenwood Genetic Center, Greenwood, SC, USAGreenwood Genetic Center, Greenwood, SC, USAMorquio syndrome A (Mucopolysaccharidosis IVA, MPS IVA) is an autosomal recessive lysosomal storage disorder caused by deficiency of N-acetyl-galactosamine-6-sulfatase (GALNS) which catabolizes the glycosaminoglycans (GAG), keratan sulfate and chondroitin-6-sulfate. Homozygous or compound heterozygous pathogenic variants in the GALNS result in the deficiency of the enzyme and consequent GAG accumulations. DNA sequence and copy number analysis of the GALNS coding region fails to identify biallelic causative pathogenic variants in up to 15% of patients with Morquio syndrome A. RNA transcript analysis was performed to identify pathogenic alterations in two unrelated families with Morquio syndrome A in whom a single heterozygous or no pathogenic alteration was detected by standard analysis of the GALNS gene. RNA sequencing and quantitative expression analysis identified the overabundance of an aberrant GALNS transcript isoform and a reduction of the clinically relevant isoform (NM_000512.4) in the Morquio syndrome A patients from both families. The aberrant isoform (ENST00000568613.1) was produced by alternative splicing and contained intronic sequence that was likely a cryptic exon predicted to result in a reading frame shift and generation of a premature termination codon. These findings indicated that the aberrant splicing is likely the novel molecular defect in our patients. RNA transcript analysis could be useful to identify pathogenic alterations and increase the yield of molecular diagnosis in patients with Morquio syndrome A whose genetic variants are not found by standard sequencing or gene dosage analysis.http://www.sciencedirect.com/science/article/pii/S2214426922000350GALNSGALNS transcript isoformAberrant splicingMorquio syndrome AMucopolysaccharidosis IVA |
| spellingShingle | Young Bae Sohn Curtis Rogers Jennifer Stallworth Jessica A. Cooley Coleman Laura Buch Erin Jozwiak Jo Ann Johnson Tim Wood Paul Harmatz Laura Pollard Raymond J. Louie RNA analysis of the GALNS transcript reveals novel pathogenic mechanisms associated with Morquio syndrome A Molecular Genetics and Metabolism Reports GALNS GALNS transcript isoform Aberrant splicing Morquio syndrome A Mucopolysaccharidosis IVA |
| title | RNA analysis of the GALNS transcript reveals novel pathogenic mechanisms associated with Morquio syndrome A |
| title_full | RNA analysis of the GALNS transcript reveals novel pathogenic mechanisms associated with Morquio syndrome A |
| title_fullStr | RNA analysis of the GALNS transcript reveals novel pathogenic mechanisms associated with Morquio syndrome A |
| title_full_unstemmed | RNA analysis of the GALNS transcript reveals novel pathogenic mechanisms associated with Morquio syndrome A |
| title_short | RNA analysis of the GALNS transcript reveals novel pathogenic mechanisms associated with Morquio syndrome A |
| title_sort | rna analysis of the galns transcript reveals novel pathogenic mechanisms associated with morquio syndrome a |
| topic | GALNS GALNS transcript isoform Aberrant splicing Morquio syndrome A Mucopolysaccharidosis IVA |
| url | http://www.sciencedirect.com/science/article/pii/S2214426922000350 |
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