REVIEW article
Front. Mol. Neurosci.
Sec. Molecular Signalling and Pathways
This article is part of the Research TopicKey Topics in Integrative Physiology - Consolidating Whole-Body Physiology Using Cutting-Edge KnowledgeView all articles
Putative role of TMEM165 in congenital cardiomyopathies
Provisionally accepted
- 1University of Aveiro, Aveiro, Portugal
- 2Universidade de Aveiro Centro de Estudos do Ambiente e do Mar, Aveiro, Portugal
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Human transmembrane protein 165 (HsTMEM165) was identified in 2012 in the context of Congenital Disorders of Glycosylation (CDG). HsTMEM165-CDG is now well established. However, cardiac symptoms are not always given the most consideration, even though they can be fatal. This review aims to summarize some of the most relevant functional properties to clarify the potential mechanisms of action that relate TMEM165 defects and the development of congenital cardiomyopathies. Within the significant worldwide causes of mortality and morbidity are congenital heart diseases. Congenital cardiomyopathies include conditions in which early diagnosis and care can improve survival and health. In general, the first diagnostic tool is clinician suspicion followed by appropriate imaging, classically an echocardiogram. Cardiomyopathies have high rates of clinically detectable genetic causes. In view of this, prompt genetic testing is highly recommended for patients with cardiomyopathy. Genetic diagnosis, that is relevant to both the patient and family members, can help guide the selection of appropriate therapies and provide valuable information about the presence of comorbidities in other organ systems. Congenital Disorders of Glycosylation (CDG) are a growing group of inherited multisystem disorders characterized by defects in the glycosylation of proteins and lipids. Hypertrophic / dilated cardiomyopathy and neuromuscular abnormalities are recurrent manifestations of glycosylation defects. Mutations within the gene encoding the human transmembrane protein 165 (HsTMEM165), that belong to uncharacterized protein family 0016 (UPF0016), have been associated with cases of CDG. Recent progress in basic and clinical research related to TMEM165, focusing on the pathogenicity of HsTMEM165 variants, are reviewed. Highlights include the critical role of amino acid replacement for maintaining the structural and functional integrity of TMEM165 and their known associations with phenotypes of CDG patients. Future directions in this rapidly evolving area of research are proposed, to recognize the potential involvement of HsTMEM165 in congenital cardiomyopathies.
Keywords: TMEM165 (human transmembrane protein 165), Ca2+/H+ antiport, cardiomyocytes, Heart, disorders of glycosylation, Congenital cardiomyopathies
Received: 01 Sep 2025; Accepted: 28 Nov 2025.
Copyright: © 2025 Polónia Gonçalves. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Maria Paula Polónia Gonçalves
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