Microphthalmia, syndromic 12 (MCOPS12)

Last updated February 13, 2023

Microphthalmia, syndromic 12 (MCOPS12) is an ultra-rare and complex neurological disease. It is caused by a single-point missense mutation in the retinoic acid receptor beta (RARB) gene. The most common disease symptoms are microphthalmia, severe (progressive) movement disorders and intellectual disability.^[1] Movement disorders may include spasticity, dystonia and chorea. In addition, malformations such as incomplete lung development (pulmonary hypoplasia), defects of the cerebellum (Chiari type I malformation), and a defect/hole in the diaphragm (diaphragmatic hernia) have been observed.^[1]^[2]

Gene

The retinoic acid receptor beta (RARB) gene (Gene ID: 5915) is located on the short (p) arm of chromosome 3 (3p24.2). It consists of 13 exons, four promoter regions and has a size of 423 kb in humans. RARB encodes retinoic acid receptor beta (RAR-beta), which belongs to the retinoic acid receptor family together with the other sub-types RAR-alpha and RAR-gamma.^[3] Several variations of the single point mutation have been identified, with mutation c.1159C>T (p.R387C) being most prominent (i.e. cytosine is replaced by thymine in nucleotide 1159 causing arginine (R) at amino acid position 387 to be replaced by cysteine (C) in RAR-beta).^[2] The respective variant impacts the disease phenotype, thus leading to heterogenous characteristics of the disease depending on the variant of the mutation.^[1]

RAR-beta is a nuclear receptor and transcription factor. Upon activation by retinoic acid (the biologically active form of vitamin A), it regulates the expression of a plethora of genes in the human body. It plays a pivotal role in the development of the embryonic digestive tract, eye, myogenesis, and brain (especially the striatum).^[4] Furthermore, RAR-beta is a tumor suppressor and hence has been in the focus of cancer therapy for almost two decades.^[5]

Research

Mutations in the RAR-beta protein lead to MCOPS12 with pleiotropic defects of an unknown cause. The mutations in RAR-beta most likely result in conformational changes of the receptor’s ligand binding domain, hence to altered ligand binding and transcriptional activity of the receptor. These could be loss of function, reduction in function, or gain of normal function.^[2]

Movement disorders are typically explained by some dysfunction in the striatum, which forms a critical part of the motor control system in the brain. Information input comes from the hindbrain by dopaminergic neurons, which connect to medium spiny neurons (MSN) in the striatum. The striatum contains two distinct types of MSNs (D1R and D2R) that carry information to different brain regions.^[4] Both D1R and D2R are dopamine receptors.

RAR-beta is a transcription factor and the D2R dopamine receptor is one of its targets. It is hypothesized that changes in RAR-beta transcriptional activity change MSN gene expression, protein composition, and metabolic activity thus leading to the observed neurological disorders.^[4]

The RAinRARE consortium federates research teams from four academic institutions to establish disease models and determine the mechanism through which mutant forms of RAR-beta affect striatum functions. Ultimately, the consortium aims to develop therapeutic approaches for MCOPS12 and robust biomarkers for monitoring the efficiency of these approaches. The teams have obtained funding by the European Union via the E-Rare platform to support this research program.

Patient advocacy

Cure MCOPS12 is a non-profit organization which was established in 2020 in Austria.^[6] Its mission is to raise awareness and fundraising to support scientific research and clinical development that will ultimately result in a cure. Amongst others, Cure MCOPS12 has funded a Natural History Study for MCOPS12 patients, which is scheduled to start in 2021.

Related Research Articles

Retinoic acid (used simplified here for all-trans-retinoic acid) is a metabolite of vitamin A₁ (all-trans-retinol) that mediates the functions of vitamin A₁ required for growth and development. All-trans-retinoic acid is required in chordate animals, which includes all higher animals from fish to humans. During early embryonic development, all-trans-retinoic acid generated in a specific region of the embryo helps determine position along the embryonic anterior/posterior axis by serving as an intercellular signaling molecule that guides development of the posterior portion of the embryo. It acts through Hox genes, which ultimately control anterior/posterior patterning in early developmental stages.

Simpson–Golabi–Behmel syndrome (SGBS), is a rare inherited congenital disorder that can cause craniofacial, skeletal, cardiac, and renal abnormalities. The syndrome is inherited in an X-linked recessive fashion, where males express the phenotype and females usually do not. Females that possess one copy of the mutation are considered to be carriers of the syndrome and may express varying degrees of the phenotype.

The thyroid hormone receptor (TR) is a type of nuclear receptor that is activated by binding thyroid hormone. TRs act as transcription factors, ultimately affecting the regulation of gene transcription and translation. These receptors also have non-genomic effects that lead to second messenger activation, and corresponding cellular response.

The retinoic acid receptor (RAR) is a type of nuclear receptor which can also act as a ligand-activated transcription factor that is activated by both all-trans retinoic acid and 9-cis retinoic acid the retinoid active derivatives of Vitamin A. They are typically found within the nucleus. There are three retinoic acid receptors (RAR), RAR-alpha, RAR-beta, and RAR-gamma, encoded by the RARA, RARB, RARG genes, respectively. Within each RAR subtype there are various isoforms differing in their N-terminal region A. Multiple splice variants have been identified in human RARs: four for RARA, five for RARB, and two for RARG. As with other type II nuclear receptors, RAR heterodimerizes with RXR and in the absence of ligand, the RAR/RXR dimer binds to hormone response elements known as retinoic acid response elements (RAREs) complexed with corepressor protein. Binding of agonist ligands to RAR results in dissociation of corepressor and recruitment of coactivator protein that, in turn, promotes transcription of the downstream target gene into mRNA and eventually protein. In addition, the expression of RAR genes is under epigenetic regulation by promoter methylation. Both the length and magnitude of the retinoid response is dependent of the degradation of RARs and RXRs through the ubiquitin-proteasome. This degradation can lead to elongation of the DNA transcription through disruption of the initiation complex or to end the response to facilitate further transcriptional programs. Due to RAR/RXR heterodimers acting as subtrates to the non steroid hormone ligand retinoid they are extensively involved in cell differentiation, proliferation, and apoptosis.

The retinoid X receptor (RXR) is a type of nuclear receptor that is activated by 9-cis retinoic acid, which is discussed controversially to be of endogenous relevance, and 9-cis-13,14-dihydroretinoic acid, which is likely to be the major endogenous mammalian RXR-selective agonist.

The RAR-related orphan receptors (RORs) are members of the nuclear receptor family of intracellular transcription factors. There are three forms of ROR, ROR-α, -β, and -γ and each is encoded by a separate gene RORA, RORB, and RORC respectively. The RORs are somewhat unusual in that they appear to bind as monomers to hormone response elements as opposed to the majority of other nuclear receptors which bind as dimers. They bind to DNA elements called ROR response elements (RORE).

The nuclear receptor 4A2 (NR4A2) also known as nuclear receptor related 1 protein (NURR1) is a protein that in humans is encoded by the NR4A2 gene. NR4A2 is a member of the nuclear receptor family of intracellular transcription factors.

Nuclear receptor TLX also known as NR2E1 is a protein that in humans is encoded by the NR2E1 gene. TLX is a member of the nuclear receptor family of intracellular transcription factors.

RAR-related orphan receptor beta (ROR-beta), also known as NR1F2 is a nuclear receptor that in humans is encoded by the RORB gene.

Rev-Erb beta (Rev-Erbβ), also known as nuclear receptor subfamily 1 group D member 2 (NR1D2), is a member of the Rev-Erb protein family. Rev-Erbβ, like Rev-Erbα, belongs to the nuclear receptor superfamily of transcription factors and can modulate gene expression through binding to gene promoters. Together with Rev-Erbα, Rev-Erbβ functions as a major regulator of the circadian clock. These two proteins are partially redundant. Current research suggests that Rev-Erbβ is less important in maintaining the circadian clock than Rev-Erbα; knock-out studies of Rev-Erbα result in significant circadian disruption but the same has not been found with Rev-Erbβ. Rev-Erbβ compensation for Rev-Erbα varies across tissues, and further research is needed to elucidate the separate role of Rev-Erbβ.

Retinoic acid receptor alpha (RAR-α), also known as NR1B1 is a nuclear receptor that in humans is encoded by the RARA gene.

Transcription factor GATA-4 is a protein that in humans is encoded by the GATA4 gene.

Retinoid X receptor gamma (RXR-gamma), also known as NR2B3 is a nuclear receptor that in humans is encoded by the RXRG gene.

Retinoid X receptor beta (RXR-beta), also known as NR2B2 is a nuclear receptor that in humans is encoded by the RXRB gene.

Retinoic acid receptor beta (RAR-beta), also known as NR1B2 is a nuclear receptor that in humans is encoded by the RARB gene.

Cellular retinoic acid-binding protein 2 is a cytoplasmic binding protein that in humans is encoded by the CRABP2 gene.

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Cytochrome c oxidase subunit 7B, mitochondrial (COX7B) is an enzyme that in humans is encoded by the COX7B gene. COX7B is a nuclear-encoded subunit of cytochrome c oxidase (COX). Cytochrome c oxidase is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane, acting as the terminal enzyme of the mitochondrial respiratory chain. Work with Oryzias latices has linked disruptions in COX7B with microphthalmia with linear skin lesions (MLS), microcephaly, and mitochondrial disease. Clinically, mutations in COX7B have been associated with linear skin defects with multiple congenital anomalies.

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References

1 2 3 Srour M, Chitayat D, Caron V, Chassaing N, Bitoun P, et al. (October 2013). "Recessive and Dominant Mutations in Retinoic Acid Receptor Beta in Cases with Microphthalmia and Diaphragmatic Hernia". American Journal of Human Genetics. 93 (4): 765–772. doi:10.1016/j.ajhg.2013.08.014. PMC 3791254 . PMID 24075189.
1 2 3 Srour M, Caron V, Pearson T, Nielsen SB, Lévesque S, Delrue MA, et al. (April 2016). "Gain-of-Function Mutations in RARB Cause Intellectual Disability with Progressive Motor Impairment". Human Mutation. 37 (8): 786–793. doi: 10.1002/humu.23004 . PMID 27120018. S2CID 22476576.
↑ di Masi A, Leboffe L, De Marinis E, Pagano F, Cicconi L, Rochette-Egly C, Lo-Coco F, Ascenzi P, Nervi C (February 2015). "Retinoic acid receptors: From molecular mechanisms to cancer therapy". Molecular Aspects of Medicine. 41: 1–115. doi:10.1016/j.mam.2014.12.003. PMID 25543955.
1 2 3 Niewiadomska-Cimicka A, Krzyżosiak A, Ye T, Podleśny-Drabiniok A, Dembélé D, Dollé P, Krężel W (July 2016). "Genome-wide Analysis of RARβ Transcriptional Targets in Mouse Striatum Links Retinoic Acid Signaling with Huntington's Disease and Other Neurodegenerative Disorders". Molecular Neurobiology. 54 (5): 3859–3878. doi:10.1007/s12035-016-0010-4. PMID 27405468. S2CID 3789489.
↑ Houle B, Rochette-Egly C, Bradley WE (February 1993). "Tumor-suppressive effect of the retinoic acid receptor beta in human epidermoid lung cancer cells". Proceedings of the National Academy of Sciences of the United States of America. 90 (3): 985–89. Bibcode:1993PNAS...90..985H. doi: 10.1073/pnas.90.3.985 . PMC 45795 . PMID 8381540.
↑ "CURE MCOPS12". CURE MCOPS12. Retrieved 18 May 2021.

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[:1-1] 1 2 3 Srour M, Chitayat D, Caron V, Chassaing N, Bitoun P, et al. (October 2013). "Recessive and Dominant Mutations in Retinoic Acid Receptor Beta in Cases with Microphthalmia and Diaphragmatic Hernia". American Journal of Human Genetics. 93 (4): 765–772. doi:10.1016/j.ajhg.2013.08.014. PMC 3791254 . PMID 24075189.

[:0-2] 1 2 3 Srour M, Caron V, Pearson T, Nielsen SB, Lévesque S, Delrue MA, et al. (April 2016). "Gain-of-Function Mutations in RARB Cause Intellectual Disability with Progressive Motor Impairment". Human Mutation. 37 (8): 786–793. doi: 10.1002/humu.23004 . PMID 27120018. S2CID 22476576.

[3] Masi A, Leboffe L, De Marinis E, Pagano F, Cicconi L, Rochette-Egly C, Lo-Coco F, Ascenzi P, Nervi C (February 2015). "Retinoic acid receptors: From molecular mechanisms to cancer therapy". Molecular Aspects of Medicine. 41: 1–115. doi:10.1016/j.mam.2014.12.003. PMID 25543955.

[:2-4] 1 2 3 Niewiadomska-Cimicka A, Krzyżosiak A, Ye T, Podleśny-Drabiniok A, Dembélé D, Dollé P, Krężel W (July 2016). "Genome-wide Analysis of RARβ Transcriptional Targets in Mouse Striatum Links Retinoic Acid Signaling with Huntington's Disease and Other Neurodegenerative Disorders". Molecular Neurobiology. 54 (5): 3859–3878. doi:10.1007/s12035-016-0010-4. PMID 27405468. S2CID 3789489.

[5] Houle B, Rochette-Egly C, Bradley WE (February 1993). "Tumor-suppressive effect of the retinoic acid receptor beta in human epidermoid lung cancer cells". Proceedings of the National Academy of Sciences of the United States of America. 90 (3): 985–89. Bibcode:1993PNAS...90..985H. doi: 10.1073/pnas.90.3.985 . PMC 45795 . PMID 8381540.

[CURE-6] "CURE MCOPS12". CURE MCOPS12. Retrieved 18 May 2021.

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