AOPEP variants as a novel cause of recessive dystonia: Generalized dystonia and dystonia-parkinsonism

Garavaglia, Barbara; Vallian, Sadeq; Romito, Luigi; Straccia, Giulia; Capecci, Marianna; Invernizzi, Federica; Andrenelli, Elisa; Kazemi, Arezu; Boesch, Sylvia; Kopajtich, Robert; Olfati, Nahid; Shariati, Mohammad; Shoeibi, Ali; Sadr‐Nabavi, Ariane; Prokisch, Holger; Winkelmann, Juliane; Zech, Michael

doi:10.1016/j.parkreldis.2022.03.007

Cited by 7 publications

(5 citation statements)

References 28 publications

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“…The WES examination performed for 14 cases revealed only a likely pathogenic variant and a VUS in the GNAL and KCNN2 genes in two cases. In our cohort, we found no differences in other frequently reported genes (AOPEP and EIF2AK2) [23]. Except for one case (VPS16), all variants considered relevant were found in patients with CD.…”

Section: Discussioncontrasting

confidence: 50%

Genetic Screening of a Hungarian Cohort with Focal Dystonia Identified Several Novel Putative Pathogenic Gene Variants

Salamon

Nagy

Pál

et al. 2023

IJMS

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Dystonia is a rare movement disorder which is characterized by sustained or intermittent muscle contractions causing abnormal and often repetitive movements, postures, or both. The two most common forms of adult-onset focal dystonia are cervical dystonia (CD) and benign essential blepharospasm (BSP). A total of 121 patients (CD, 74; BSP, 47) were included in the study. The average age of the patients was 64 years. For the next-generation sequencing (NGS) approach, 30 genes were selected on the basis of a thorough search of the scientific literature. Assessment of 30 CD- and BSP-associated genes from 121 patients revealed a total of 209 different heterozygous variants in 24 genes. Established clinical and genetic validity was determined for nine heterozygous variations (three likely pathogenic and six variants of uncertain significance). Detailed genetic examination is an important part of the work-up for focal dystonia forms. To our knowledge, our investigation is the first such study to be carried out in the Middle-European region.

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Section: Discussioncontrasting

confidence: 50%

Genetic Screening of a Hungarian Cohort with Focal Dystonia Identified Several Novel Putative Pathogenic Gene Variants

Salamon

Nagy

Pál

et al. 2023

IJMS

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“…4 Follow-up with this subject might not only be relevant for counseling the patient and his family, might also provide insight into the variability of age at onset in this rare disorder. Differences regarding age at onset were also observed in two previously reported pairs of siblings in which each pair had the same genetic mutation, but had a different site 2 and age at onset 2,5 (difference at onset of 2 and 5 years, respectively). The variability of age at disease-onset should be considered when counseling patients with AOPEP-associated dystonia, asymptomatic mutation carriers, and their families.…”

supporting

confidence: 63%

“…A certain methyl group donation capacity also exists centrally, but homocysteine concentration as the main biomarker for the need of methyl groups was found elevated in the cerebrospinal fluid of long-term L-dopa-/DDI-treated patients. 5 Homocysteine increases when the endogenous, abundant amino acid methionine acts as a methyl group donor for COMT-mediated Ldopa degradation. This process demands a methyl group transfer from the donor S-adenosylmethionine.…”

Section: An Indirect Proof For Levodopa-induced Vitamin Deficiency In...mentioning

confidence: 99%

Variable Age at Onset in AOPEP‐Associated Dystonia

Minnerop,

Leube,

Reinhardt

et al. 2023

Movement Disorders

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“…Observational studies have shown that Lachnospiraceae and Aminopeptidase O Protein co-regulate angiotensin and muscle metabolism (Bai et al, 2021 ; Bajaj et al, 2021 ; Schulz et al, 2021 ; Sun et al, 2021 ). Additionally, research has identified pathogenic genes related to muscle atrophy, such as AOPEP (Fevga et al, 2022 ; Garavaglia et al, 2022 ; Menden et al, 2022 ; Zech et al, 2022 ; Lin et al, 2023 ; Thomsen et al, 2023 ), suggesting a potential novel approach for patients with cachexia to improve muscle symptoms by altering the composition of gut microbiota. Both investigations adopted an observational design.…”

Section: Discussionmentioning

confidence: 99%

“…This protein plays a role in the generation of angiotensin in the renin-angiotensin system, and its associated pathways include peptide hormone metabolism and muscle protein metabolism (Wu et al, 2011 ). Mutations in AOPEP were found to be associated with muscle atrophy and impaired muscle tone in a large-scale multicenter study (Fevga et al, 2022 ; Garavaglia et al, 2022 ; Zech et al, 2022 ; Lin et al, 2023 ). However, the mechanism by which AOPEP acts on ALM is currently unclear.…”

Section: Discussionmentioning

confidence: 99%

Aminopeptidase O Protein mediates the association between Lachnospiraceae and appendicular lean mass

Gao,

Zhou,

Chen

et al. 2024

Front. Microbiol.

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ObjectiveInvestigating the causal relationship between Lachnospiraceae and Appendicular lean mass (ALM) and identifying and quantifying the role of Aminopeptidase O Protein (AOPEP) as a potential mediator.MethodsThe summary statistics data of gut microbiota composition from the largest available genome-wide association study (GWAS) meta-analysis conducted by the MiBioGen Consortium (n = 13,266). Appendicular lean mass data were obtained from the UK-Biobank (n = 450,243). We conducted bidirectional two-sample Mendelian randomization (MR) analysis using summary-level data from GWAS to investigate the causal relationship between Lachnospiraceae and ALM. Additionally, we employed a drug-targeted MR approach to assess the causal relationship between AOPEP and ALM. Finally, a two-step MR was employed to quantitatively estimate the proportion of the effect of Lachnospiraceae on ALM that is mediated by AOPEP. Cochran's Q statistic was used to quantify heterogeneity among instrumental variable estimates.ResultsIn the MR analysis, it was found that an increase in genetically predicted Lachnospiraceae [OR = 1.031, 95% CI (1.011–1.051), P = 0.002] is associated with an increase in ALM. There is no strong evidence to suggest that genetically predicted ALM has an impact on Lachnospiraceae genus [OR = 1.437, 95% CI (0.785–2.269), P = 0.239]. The proportion of genetically predicted Lachnospiraceae mediated by AOPEP was 34.2% [95% CI (1.3%−67.1%)].ConclusionOur research reveals that increasing Lachnospiraceae abundance in the gut can directly enhance limb muscle mass and concurrently suppress AOPEP, consequently mitigating limb muscle loss. This supports the potential therapeutic modulation of gut microbiota for sarcopenia. Interventions such as drug treatments or microbiota transplantation, aimed at elevating Lachnospiraceae abundance and AOPEP inhibition, synergistically improve sarcopenia in the elderly, thereby enhancing the overall quality of life for older individuals.

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AOPEP variants as a novel cause of recessive dystonia: Generalized dystonia and dystonia-parkinsonism

Cited by 7 publications

References 28 publications

Genetic Screening of a Hungarian Cohort with Focal Dystonia Identified Several Novel Putative Pathogenic Gene Variants

Genetic Screening of a Hungarian Cohort with Focal Dystonia Identified Several Novel Putative Pathogenic Gene Variants

Variable Age at Onset in AOPEP‐Associated Dystonia

Aminopeptidase O Protein mediates the association between Lachnospiraceae and appendicular lean mass

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