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Article

New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform

1
Fundació de Recerca de l’Institut de Microcirurgia Ocular, 08035 Barcelona, Spain
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Department of Genetics, Institut de Microcirurgia Ocular (IMO), 08035 Barcelona, Spain
3
Department of Pediatric Ophthalmology, Strabismus and Neurophthalmology, Institut de Microcirurgia Ocular (IMO), 08035 Barcelona, Spain
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Pediatric Metabolic Unit and Neuropediatrics, Hospital Universitari Son Espases, 07120 Palma de Mallorca, Spain
5
Department of Retina, Institut de Microcirurgia Ocular (IMO), 08035 Barcelona, Spain
*
Authors to whom correspondence should be addressed.
Academic Editor: Tamar Ben-Yosef
Int. J. Mol. Sci. 2021, 22(5), 2262; https://doi.org/10.3390/ijms22052262
Received: 31 January 2021 / Revised: 18 February 2021 / Accepted: 21 February 2021 / Published: 24 February 2021
(This article belongs to the Special Issue Inherited Retinal Diseases)
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 (NMNAT1) 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 NMNAT1 isoform, which is variably expressed in healthy human tissues. Altogether, these findings represent new evidence of the correlation of NMNAT1 and SHILCA syndrome, and provide additional insights into the healthy and pathogenic expression of this gene. View Full-Text
Keywords: Leber congenital amaurosis (LCA); spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and Leber congenital amaurosis (SHILCA); nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1); transcriptional alteration; inherited retinal diseases; macular coloboma; developmental delay; hypomyelination; sensorineural hearing loss; spondylo-epiphyseal dysplasia Leber congenital amaurosis (LCA); spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and Leber congenital amaurosis (SHILCA); nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1); transcriptional alteration; inherited retinal diseases; macular coloboma; developmental delay; hypomyelination; sensorineural hearing loss; spondylo-epiphyseal dysplasia
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MDPI and ACS Style

Abad-Morales, V.; Wert, A.; Ruiz Gómez, M.Á.; Navarro, R.; Pomares, E. New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform. Int. J. Mol. Sci. 2021, 22, 2262. https://doi.org/10.3390/ijms22052262

AMA Style

Abad-Morales V, Wert A, Ruiz Gómez MÁ, Navarro R, Pomares E. New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform. International Journal of Molecular Sciences. 2021; 22(5):2262. https://doi.org/10.3390/ijms22052262

Chicago/Turabian Style

Abad-Morales, Víctor, Ana Wert, María Á. Ruiz Gómez, Rafael Navarro, and Esther Pomares. 2021. "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform" International Journal of Molecular Sciences 22, no. 5: 2262. https://doi.org/10.3390/ijms22052262

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