The melanocortin receptors (MCRs) and their accessory proteins (MRAPs) are involved in regulation of a diverse range of endocrine pathways. Genetic variants of these components result in phenotypic variation and disease. The MC1R is expressed in skin and variants in the MC1R gene are associated with ginger hair color. The MC2R mediates the action of ACTH in the adrenal gland to stimulate glucocorticoid production and MC2R mutations result in familial glucocorticoid deficiency (FGD). MC3R and MC4R are involved in metabolic regulation and their gene variants are associated with severe pediatric obesity, whereas the function of MC5R remains to be fully elucidated. MRAPs have been shown to modulate the function of MCRs and genetic variants in MRAPs are associated with diseases including FGD type 2 and potentially early onset obesity. This review provides an insight into recent advances in MCRs and MRAPs physiology, focusing on the disorders associated with their dysfunction.
Autosomal dominant optic atrophy (DOA) is the most common inherited optic neuropathy in the United Kingdom. DOA has an insidious onset in early childhood, typically presenting with bilateral, central visual loss caused by the preferential loss of retinal ganglion cells. 60%–70% of genetically confirmed DOA cases are associated with variants in
OPA1
, a ubiquitously expressed GTPase that regulates mitochondrial homeostasis through coordination of inner membrane fusion, maintenance of cristae structure, and regulation of bioenergetic output. Whether genetic correction of
OPA1
pathogenic variants can alleviate disease-associated phenotypes remains unknown. Here, we demonstrate generation of patient-derived
OPA1
c.1334G>A: p.R445H mutant induced pluripotent stem cells (iPSCs), followed by correction of
OPA1
through CRISPR-Cas9-guided homology-directed repair (HDR) and evaluate the effect of
OPA1
correction on mitochondrial homeostasis. CRISPR-Cas9 gene editing demonstrated an efficient method of
OPA1
correction, with successful gene correction in 57% of isolated iPSCs. Correction of
OPA1
restored mitochondrial homeostasis, re-establishing the mitochondrial network and basal respiration and ATP production levels. In addition, correction of
OPA1
re-established the levels of wild-type (WT) mitochondrial DNA (mtDNA) and reduced susceptibility to apoptotic stimuli. These data demonstrate that nuclear gene correction can restore mitochondrial homeostasis and improve mtDNA integrity in DOA patient-derived cells carrying an
OPA1
variant.
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