Linkage analysis and whole exome sequencing reveals AHNAK2 as a novel genetic cause for autosomal recessive CMT in a Malaysian family

Tey, Shelisa; Shahrizaila, Nortina; Drew, Alexander P.; Samulong, Sarimah; Goh, Kim‐Leng; Battaloğlu, Esra; Atkinson, Derek; Parman, Yeşim; Jordanova, Albena; Chung, Ki Wha; Choi, Byung‐Ok; Li, Yi-Chung; Auer‐Grumbach, Michaela; Nicholson, Garth A.; Kennerson, Marina; Ahmad‐Annuar, Azlina

doi:10.1007/s10048-019-00576-3

Cited by 11 publications

(12 citation statements)

References 33 publications

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“…AHNAK has been identified as a biomarker in several, including metastatic, cancers (166)(167)(168)(169) and linked to drug resistance in cancer in association with viral infection (170). AHNAK has been is also related to stress-induced secretion of FGF1-a growth factor regulating carcinogenesis, angiogenesis, and inflammation (171) and to inherited peripheral neuropathy (172). AHNAK was previously identified to be deiminated in aggressive glioblastoma cells by our group (27,61).…”

Section: Discussionmentioning

confidence: 99%

Deimination Protein Profiles in Alligator mississippiensis Reveal Plasma and Extracellular Vesicle-Specific Signatures Relating to Immunity, Metabolic Function, and Gene Regulation

et al. 2020

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Alligators are crocodilians and among few species that endured the Cretaceous-Paleogene extinction event. With long life spans, low metabolic rates, unusual immunological characteristics, including strong antibacterial and antiviral ability, and cancer resistance, crocodilians may hold information for molecular pathways underlying such physiological traits. Peptidylarginine deiminases (PADs) are a group of calcium-activated enzymes that cause posttranslational protein deimination/citrullination in a range of target proteins contributing to protein moonlighting functions in health and disease. PADs are phylogenetically conserved and are also a key regulator of extracellular vesicle (EV) release, a critical part of cellular communication. As little is known about PAD-mediated mechanisms in reptile immunology, this study was aimed at profiling EVs and protein deimination in Alligator mississippiensis. Alligator plasma EVs were found to be polydispersed in a 50-400-nm size range. Key immune, metabolic, and gene regulatory proteins were identified to be posttranslationally deiminated in plasma and plasma EVs, with some overlapping hits, while some were unique to either plasma or plasma EVs. In whole plasma, 112 target proteins were identified to be deiminated, while 77 proteins were found as deiminated protein hits in plasma EVs, whereof 31 were specific for EVs only, including proteins specific for gene regulatory functions (e.g., histones). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed KEGG pathways specific to deiminated proteins in whole plasma related to adipocytokine signaling, while KEGG pathways of deiminated proteins specific to EVs included ribosome, biosynthesis of amino acids, and glycolysis/gluconeogenesis pathways as well as core histones. This highlights roles for EV-mediated export of deiminated protein cargo with roles in metabolism and gene regulation, also related to cancer. The identification of posttranslational deimination and EV-mediated communication Criscitiello et al. Deimination and EV Signatures in Alligator in alligator plasma revealed here contributes to current understanding of protein moonlighting functions and EV-mediated communication in these ancient reptiles, providing novel insight into their unusual immune systems and physiological traits. In addition, our findings may shed light on pathways underlying cancer resistance, antibacterial and antiviral resistance, with translatable value to human pathologies.

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Section: Discussionmentioning

confidence: 99%

Deimination Protein Profiles in Alligator mississippiensis Reveal Plasma and Extracellular Vesicle-Specific Signatures Relating to Immunity, Metabolic Function, and Gene Regulation

et al. 2020

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“…This means that PRX and AHNAK2 are likely to add stability and order to large molecular complexes through this interaction. With this dimerisation, it can be hypothesised that, like AHNAK and PRX, AHNAK2 may have a myelination maintenance role and that mutations in AHNAK2 could disrupt this specific interaction with PRX [8,10,40]. Furthermore, PRX mutations result in various demyelinating peripheral neuropathies, such as Charcot-Marie-Tooth (CMT) disease and Dejerne-Sottas disease, again reflecting PRX's major role in the myelination of peripheral nerves [10,41].…”

Section: Ahnak2 In Normal Tissuementioning

confidence: 99%

The Obscure Potential of AHNAK2

Zardab

Stasinos

Grose

et al. 2022

Cancers

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AHNAK2 is a protein discovered in 2004, with a strong association with oncogenesis in various epithelial cancers. It has a large 616 kDa tripartite structure and is thought to take part in the formation of large multi-protein complexes. High expression is found in clear cell renal carcinoma, pancreatic ductal adenocarcinoma, uveal melanoma, and lung adenocarcinoma, with a relation to poor prognosis. Little work has been done in exploring the function and relation AHNAK2 has with cancer, with early studies showing promising potential as a future biomarker and therapeutic target.

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“…However, the number of families identified in the initial and follow-on papers is typically low; for example, Tey et al recently identified AHNAK2 to be the causative gene for AR CMT in a single family, and analysis of whole exome sequencing (WES) from 115 unsolved families led to one additional family demonstrating segregation of a different variant in the same gene. 8 In 2013, Gonzalez et al reported a single family with a mutation in MARS causative for CMT2 with no additional evidence in 400 additional families. Three additional families have since been identified harboring likely pathogenic variants in this gene.…”

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confidence: 99%

Genetic modifiers and non-Mendelian aspects of CMT

2020

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Charcot-Marie-Tooth (CMT) neuropathies are amongst the most common inherited diseases in neurology. While great strides have been made to identify the genesis of these diseases, a diagnostic gap of 30-60% remains. Classic models of genetic causation may be limited to fully close this gap and, thus, we review the current state and future role of alternative, non-Mendelian forms of genetics in CMT. Promising synergies exist to further define the full genetic architecture of inherited neuropathies, including affordable whole-genome sequencing, increased data aggregation and clinical collaboration, improved bioinformatics and statistical methodology, and vastly improved computational resources. Given the recent advances in genetic therapies for rare diseases, it becomes a matter of urgency to diagnose CMT patients with great fidelity. Otherwise, they will not be able to benefit from such therapeutic options, or worse, suffer harm when pathogenicity of genetic variation is falsely evaluated. In addition, the newly identified modifier and risk genes may offer alternative targets for pharmacotherapy of inherited and, potentially, even acquired forms of neuropathies. Genetics of Charcot-Marie-Tooth DiseaseAs with many other Mendelian diseases, the introduction of next generation sequencing (NGS) revolutionized the genetic diagnosis of Charcot-Marie-Tooth disease with now over 90 known genes causing CMT. 1,2 Though CMT can be caused by an overwhelming amount of genetic defects, it is noteworthy that a handful of genes are responsible for the majority of cases. More than half of all CMT cases are caused by five genetic mutations: PMP22 duplication (39.5%), PMP22 point mutation (1.4%), GJB1 (10.8%), MFN2 (2.8%), and MPZ (3.1%). 3 For autosomal dominant (AD) demyelinating CMT (CMT1), the most commonly mutated genes are: GJB1, PMP22, MPZ, EGR2, LITAF, NEFL, or PMP2. 3 Unlike CMT1, AD axonal CMT (CMT2) and autosomal recessive (AR) axonal and/or demyelinating forms (CMT4) are caused by many, individually rare, genes that typically

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Linkage analysis and whole exome sequencing reveals AHNAK2 as a novel genetic cause for autosomal recessive CMT in a Malaysian family

Cited by 11 publications

References 33 publications

Deimination Protein Profiles in Alligator mississippiensis Reveal Plasma and Extracellular Vesicle-Specific Signatures Relating to Immunity, Metabolic Function, and Gene Regulation

Deimination Protein Profiles in Alligator mississippiensis Reveal Plasma and Extracellular Vesicle-Specific Signatures Relating to Immunity, Metabolic Function, and Gene Regulation

The Obscure Potential of AHNAK2

Genetic modifiers and non-Mendelian aspects of CMT

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