New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the <i>NMNAT1</i> Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform
This study aims to genetically characterize a two-year-old patient suffering from multiple systemic abnormalities, including skeletal, nervous and developmental involvements and Leber congenital amaurosis (LCA). Genetic screening by next-generation sequencing identified two heterozygous pathogenic v...
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MDPI AG
2021-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/5/2262 |
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| author | Víctor Abad-Morales Ana Wert María Ángeles Ruiz Gómez Rafael Navarro Esther Pomares |
| author_facet | Víctor Abad-Morales Ana Wert María Ángeles Ruiz Gómez Rafael Navarro Esther Pomares |
| author_sort | Víctor Abad-Morales |
| collection | DOAJ |
| description | This study aims to genetically characterize a two-year-old patient suffering from multiple systemic abnormalities, including skeletal, nervous and developmental involvements and Leber congenital amaurosis (LCA). Genetic screening by next-generation sequencing identified two heterozygous pathogenic variants in nicotinamide mononucleotide adenylyltransferase 1 (<i>NMNAT1</i>) as the molecular cause of the disease: c.439+5G>T and c.299+526_*968dup.This splice variant has never been reported to date, whereas pathogenic duplication has recently been associated with cases displaying an autosomal recessive disorder that includes a severe form of spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and LCA (SHILCA), as well as some brain anomalies. Our patient presented clinical manifestations which correlated strongly with this reported syndrome. To further study the possible transcriptional alterations resulting from these mutations, mRNA expression assays were performed in the patient and her father. The obtained results detected aberrant alternative transcripts and unbalanced levels of expression, consistent with severe systemic involvement. Moreover, these analyses also detected a novel <i>NMNAT1</i> isoform, which is variably expressed in healthy human tissues. Altogether, these findings represent new evidence of the correlation of <i>NMNAT1</i> and SHILCA syndrome, and provide additional insights into the healthy and pathogenic expression of this gene. |
| first_indexed | 2024-03-09T00:34:44Z |
| format | Article |
| id | doaj.art-9e9a6e3939a44f2990145fbf4a7b1169 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T00:34:44Z |
| publishDate | 2021-02-01 |
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| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-9e9a6e3939a44f2990145fbf4a7b11692023-12-11T18:17:53ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-02-01225226210.3390/ijms22052262New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the <i>NMNAT1</i> Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative IsoformVíctor Abad-Morales0Ana Wert1María Ángeles Ruiz Gómez2Rafael Navarro3Esther Pomares4Fundació de Recerca de l’Institut de Microcirurgia Ocular, 08035 Barcelona, SpainFundació de Recerca de l’Institut de Microcirurgia Ocular, 08035 Barcelona, SpainPediatric Metabolic Unit and Neuropediatrics, Hospital Universitari Son Espases, 07120 Palma de Mallorca, SpainFundació de Recerca de l’Institut de Microcirurgia Ocular, 08035 Barcelona, SpainFundació de Recerca de l’Institut de Microcirurgia Ocular, 08035 Barcelona, SpainThis study aims to genetically characterize a two-year-old patient suffering from multiple systemic abnormalities, including skeletal, nervous and developmental involvements and Leber congenital amaurosis (LCA). Genetic screening by next-generation sequencing identified two heterozygous pathogenic variants in nicotinamide mononucleotide adenylyltransferase 1 (<i>NMNAT1</i>) as the molecular cause of the disease: c.439+5G>T and c.299+526_*968dup.This splice variant has never been reported to date, whereas pathogenic duplication has recently been associated with cases displaying an autosomal recessive disorder that includes a severe form of spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and LCA (SHILCA), as well as some brain anomalies. Our patient presented clinical manifestations which correlated strongly with this reported syndrome. To further study the possible transcriptional alterations resulting from these mutations, mRNA expression assays were performed in the patient and her father. The obtained results detected aberrant alternative transcripts and unbalanced levels of expression, consistent with severe systemic involvement. Moreover, these analyses also detected a novel <i>NMNAT1</i> isoform, which is variably expressed in healthy human tissues. Altogether, these findings represent new evidence of the correlation of <i>NMNAT1</i> and SHILCA syndrome, and provide additional insights into the healthy and pathogenic expression of this gene.https://www.mdpi.com/1422-0067/22/5/2262Leber congenital amaurosis (LCA)spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and Leber congenital amaurosis (SHILCA)nicotinamide mononucleotide adenylyltransferase 1 (<i>NMNAT1</i>)transcriptional alterationinherited retinal diseasesmacular coloboma |
| spellingShingle | Víctor Abad-Morales Ana Wert María Ángeles Ruiz Gómez Rafael Navarro Esther Pomares New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the <i>NMNAT1</i> Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform International Journal of Molecular Sciences Leber congenital amaurosis (LCA) spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and Leber congenital amaurosis (SHILCA) nicotinamide mononucleotide adenylyltransferase 1 (<i>NMNAT1</i>) transcriptional alteration inherited retinal diseases macular coloboma |
| title | New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the <i>NMNAT1</i> Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform |
| title_full | New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the <i>NMNAT1</i> Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform |
| title_fullStr | New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the <i>NMNAT1</i> Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform |
| title_full_unstemmed | New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the <i>NMNAT1</i> Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform |
| title_short | New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the <i>NMNAT1</i> Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform |
| title_sort | new insights on the genetic basis underlying shilca syndrome characterization of the i nmnat1 i pathological alterations due to compound heterozygous mutations and identification of a novel alternative isoform |
| topic | Leber congenital amaurosis (LCA) spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and Leber congenital amaurosis (SHILCA) nicotinamide mononucleotide adenylyltransferase 1 (<i>NMNAT1</i>) transcriptional alteration inherited retinal diseases macular coloboma |
| url | https://www.mdpi.com/1422-0067/22/5/2262 |
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