SOD1 D91A variant in the southernmost tip of Europe: a heterozygous ALS patient resident on the island of Gozo

Wismayer, Maia Farrugia; Wismayer, Andrew Farrugia; Pace, Adrian; Vassallo, Neville; Cauchi, Ruben J.

doi:10.1038/s41431-021-00975-x

Cited by 5 publications

(3 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This can be attributed to the admixture of Maltese inhabitants with other populations from Mediterranean and Northern European regions that colonised Malta in the past, as well as the recent admixture due to migrations from Africa and Asia, which has subsequently overcome the geographical barriers [ 80 , 81 , 82 ]. Other studies have supported the hypothesis of a founder effect in the Maltese population [ 83 , 84 , 85 , 86 ].…”

Section: Discussionmentioning

confidence: 66%

Whole Genome Sequencing Unravels New Genetic Determinants of Early-Onset Familial Osteoporosis and Low BMD in Malta

Cilia

Friggieri

Vassallo

et al. 2022

Genes

View full text Add to dashboard Cite

Background: Osteoporosis is a skeletal disease with a strong genetic background. The study aimed to identify the genetic determinants of early-onset familial osteoporosis and low bone mineral density (BMD) in a two-generation Maltese family. Methods: Fifteen relatives aged between 28–74 years were recruited. Whole genome sequencing was conducted on 12 relatives and shortlisted variants were genotyped in the Malta Osteoporotic Fracture Study (MOFS) for replication. Results: Sequential variant filtering following a dominant inheritance pattern identified rare missense variants within SELP, TGF-β2 and ADAMTS20, all of which were predicted to be likely pathogenic and participate in osteoimmunology. TGF-β2 c.1136C>T was identified in five individuals from the MOFS in heterozygosity, four of whom had osteopenia/osteoporosis at the lumbar spine and hip, and/or had sustained a low-trauma fracture. Heterozygosity for the ADAMTS20 c.4090A>T was accompanied by lower total hip BMD (p = 0.018) and lower total serum calcium levels in MOFS (p < 0.01), recapitulating the findings from the family. Women carrying at least one copy of the alternative allele (TC/CC) for SELP c.2177T>C exhibited a tendency for lower lumbar spine BMD and/or wrist fracture history relative to women with TT genotype. Conclusions: Our findings suggest that the identified variants, alone or in combination, could be causal factors of familial osteoporosis and low BMD, requiring replication in larger collections.

show abstract

Section: Discussionmentioning

confidence: 66%

Whole Genome Sequencing Unravels New Genetic Determinants of Early-Onset Familial Osteoporosis and Low BMD in Malta

Cilia

Friggieri

Vassallo

et al. 2022

Genes

View full text Add to dashboard Cite

show abstract

“…A wide range of clinical symptoms were observed in ALS cases carrying SOD1 mutations, from the classic ALS phenotypes with the involvement of upper and lower motor neurons to progressive muscular atrophy to mixed phenotypes of ALS and neurodegenerative diseases [ 15 ]. Specific SOD1 mutations were found to be associated with distinct clinical phenotypes [ 35 , 36 , 37 , 38 ]. For example, the G41S mutation showed a significantly shorter survival time and faster progression while the L144S SOD1 mutation showed a longer survival and slower disease progression compared to other tested mutations, such as K3E, L126* and N139D [ 15 ].…”

Section: Sod1 Alsmentioning

confidence: 99%

Updates on Disease Mechanisms and Therapeutics for Amyotrophic Lateral Sclerosis

Nguyen

2024

Cells

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, is a motor neuron disease. In ALS, upper and lower motor neurons in the brain and spinal cord progressively degenerate during the course of the disease, leading to the loss of the voluntary movement of the arms and legs. Since its first description in 1869 by a French neurologist Jean-Martin Charcot, the scientific discoveries on ALS have increased our understanding of ALS genetics, pathology and mechanisms and provided novel therapeutic strategies. The goal of this review article is to provide a comprehensive summary of the recent findings on ALS mechanisms and related therapeutic strategies to the scientific audience. Several highlighted ALS research topics discussed in this article include the 2023 FDA approved drug for SOD1 ALS, the updated C9orf72 GGGGCC repeat-expansion-related mechanisms and therapeutic targets, TDP-43-mediated cryptic splicing and disease markers and diagnostic and therapeutic options offered by these recent discoveries.

show abstract

“…Prevalence of p.D91A in ALS cases varies globally and is distinctly absent in some populations ( , accessed on 22 October 2021). In particular, this is the most prevalent variant in Europe [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Individual Oligogenic Background in p.D91A-SOD1 Amyotrophic Lateral Sclerosis Patients

Gentile

Perrone

Morello

et al. 2021

Genes

View full text Add to dashboard Cite

The p.D91A is one of the most common ALS-causing SOD1 mutations and is known to be either recessive or dominant. The homozygous phenotype is characterized by prolonged survival and slow progression of disease, whereas the affected heterozygous phenotypes can vary. To date, no genetic protective factors located close to SOD1 have been associated with the mild progressive homozygous phenotype. Using Next Generation Sequencing (NGS), we characterized a small cohort of sporadic and familial p.D91A-SOD1 heterozygous (n = 2) or homozygous (n = 5) ALS patients, to reveal any additional contributing variant in 39 ALS-related genes. We detected unique sets of non-synonymous variants, four of which were of uncertain significance and several in untranslated regions of ALS-related genes. Our results supported an individual oligogenic background underlying both sporadic and familial p.D91A cases irrespective of their p.D91A mutant alleles. We suggest that a comprehensive genomic view of p.D91A-SOD1 ALS patients may be useful in identifying emerging variants and improving disease diagnosis as well as guiding precision medicine.

show abstract

SOD1 D91A variant in the southernmost tip of Europe: a heterozygous ALS patient resident on the island of Gozo

Cited by 5 publications

References 15 publications

Whole Genome Sequencing Unravels New Genetic Determinants of Early-Onset Familial Osteoporosis and Low BMD in Malta

Whole Genome Sequencing Unravels New Genetic Determinants of Early-Onset Familial Osteoporosis and Low BMD in Malta

Updates on Disease Mechanisms and Therapeutics for Amyotrophic Lateral Sclerosis

Individual Oligogenic Background in p.D91A-SOD1 Amyotrophic Lateral Sclerosis Patients

Contact Info

Product

Resources

About