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Alpha-mannosidosis in Tunisian consanguineous families: Potential involvement of variants in GHR and SLC19A3 genes in the variable expressivity of cognitive impairment
- Source :
- PLoS ONE, PLoS ONE, 2021, 16 (10), pp.e0258202. ⟨10.1371/journal.pone.0258202⟩, PLoS ONE, Vol 16, Iss 10, p e0258202 (2021)
- Publication Year :
- 2021
- Publisher :
- HAL CCSD, 2021.
-
Abstract
- Alpha-Mannosidosis (AM) is an ultra-rare storage disorder caused by a deficiency of lysosomal alpha-mannosidase encoded by the MAN2B1 gene. Clinical presentation of AM includes mental retardation, recurrent infections, hearing loss, dysmorphic features, and motor dysfunctions. AM has never been reported in Tunisia. We report here the clinical and genetic study of six patients from two Tunisian families with AM. The AM diagnosis was confirmed by an enzymatic activity assay. Genetic investigation was conducted by Sanger sequencing of the mutational hotspots for the first family and by ES analysis for the second one. In the first family, a frameshift duplication p.(Ser802GlnfsTer129) was identified in the MAN2B1 gene. For the second family, ES analysis led to the identification of a missense mutation p.(Arg229Trp) in the MAN2B1 gene in four affected family members. The p.(Ser802GlnfsTer129) mutation induces a premature termination codon which may trigger RNA degradation by the NMD system. The decrease in the levels of MAN2B1 synthesis could explain the severe phenotype observed in the index case. According to the literature, the p.(Arg229Trp) missense variant does not have an impact on MAN2B1 maturation and transportation, which correlates with a moderate clinical sub-type. To explain the intra-familial variability of cognitive impairment, exome analysis allowed the identification of two likely pathogenic variants in GHR and SLC19A3 genes potentially associated to cognitive decline. The present study raises awareness about underdiagnosis of AM in the region that deprives patients from accessing adequate care. Indeed, early diagnosis is critical in order to prevent disease progression and to propose enzyme replacement therapy.
- Subjects :
- Male
MESH: Geography
[SDV]Life Sciences [q-bio]
Otology
Deafness
MESH: Base Sequence
MESH: Cognitive Dysfunction
MESH: Membrane Transport Proteins
Consanguinity
Database and Informatics Methods
Medical Conditions
MESH: Audiometry
Gene duplication
Medicine and Health Sciences
Missense mutation
Cognitive decline
Hearing Disorders
Exome
Cognitive Impairment
Sanger sequencing
Genetics
Multidisciplinary
Geography
Cognitive Neurology
MESH: Genetic Predisposition to Disease
Genomics
Genomic Databases
Pedigree
Phenotype
Neurology
symbols
Medicine
Female
Cellular Structures and Organelles
MESH: Tunisia
Research Article
Tunisia
MESH: Mutation
MESH: Exome Sequencing
MESH: Pedigree
Science
Cognitive Neuroscience
Disabilities
Alpha-mannosidosis
MESH: Carrier Proteins
MESH: alpha-Mannosidosis
Biology
Research and Analysis Methods
MESH: Phenotype
Frameshift mutation
symbols.namesake
Audiometry
Intellectual Disability
Exome Sequencing
medicine
Humans
Cognitive Dysfunction
Family
Genetic Predisposition to Disease
MESH: Family
MESH: Consanguinity
MESH: Humans
Base Sequence
Membrane Transport Proteins
Biology and Life Sciences
Computational Biology
Human Genetics
Cell Biology
Genome Analysis
medicine.disease
Human genetics
MESH: Male
Biological Databases
Otorhinolaryngology
Mutation
alpha-Mannosidosis
Mutation Databases
Cognitive Science
Carrier Proteins
Lysosomes
MESH: Female
Neuroscience
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Database :
- OpenAIRE
- Journal :
- PLoS ONE, PLoS ONE, 2021, 16 (10), pp.e0258202. ⟨10.1371/journal.pone.0258202⟩, PLoS ONE, Vol 16, Iss 10, p e0258202 (2021)
- Accession number :
- edsair.doi.dedup.....f10eed9fa8dee83d1c67ef18ba710098