Deciphering the Etiology of Rare Genetic Disorders Associated with Protein Phosphatases

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Background

The reversible phosphorylation of proteins controls nearly all signal transduction pathways in human cells. Therefore, it is not surprising that aberrations in reversible phosphorylation have been linked to many forms of disease, including cancer, diabetes, and developmental disorders. In mammals there are two major families of protein kinases (serine/threonine kinases and tyrosine kinases) catalyzing protein phosphorylation. The kinases are countered by two major families of protein phosphatases (serine/threonine protein phosphatases and tyrosine phosphatases) that are highly conserved among species. When compared to their kinase counterparts, to date, the role of protein phosphatases in disorders and disease has received less attention. However, advances in DNA sequencing technologies and functional genomic approaches have allowed the discovery of a plethora of novel genetic disorders, and emerging evidence indicates that phosphatases play many critical roles.

To accurately determine how rare pathogenic genomic variants alter normal biology, clinical characteristics need to be linked to altered biological processes. These characteristics may manifest at the molecular level, cellular level, or level of tissue and organ systems. Thus, diverse techniques are required to reveal how the variant protein differs structurally and functionally from the wild-type protein. Often this requires studies to first reveal previously unknown biological functions of the wild-type protein. Furthermore, studies may also be needed to reveal the processes controlling the protein’s expression and intracellular location, or, if the protein functions as an enzyme, the control of its catalytic activity.

Such efforts have been greatly aided by recent advances in genomic editing and protein expression technologies, which have allowed the rapid development of cell lines and animal models. Advances in RNAseq, global-proteomics, -phosphoproteomics, -metabolomics, and -lipidomics have provided opportunity for non-biased analyses of how the variant proteins alter normal function, including insights into altered cell signaling. Combining in-cell discovery methods with in vitro validation studies and clinical characteristics allows distinction between direct and indirect effects. Together, such studies can reveal the underlying etiology of a rare genetic disorder and sometimes common pathways shared by other rare genetic disorders.

The objective of this topic is to create a “road map” that will help decipher the etiology of rare genetic disorders associated with developmental delay and altered phosphorylation. We invite the submission of original studies, mini-reviews, reviews, perspectives, or commentaries on topics including (but not limited to):

• Identification of disorders caused by variations in phosphatases
• Structural and biochemical studies to determine how the variant alters the normal function of the protein
• Methods and procedures to help diagnose the disorder and characterize the clinical syndrome
• Identification of common signaling pathways among disorders of altered phosphorylation
• Identification of molecular mechanisms that contribute to the disorder

Particular attention will be given to studies with demonstrated or hypothesized functional consequences that can account for the pathology associated with the human phenotypes.

Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

Keywords: rare genetic disorders, kinases, phosphatases, signal transduction, developmental delay

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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