RARB – MCOPS12 (Syndromic microphthalmia 12)

Dominant RARB variants underlie MCOPS12, a syndromic form of microphthalmia associated with variable birth anomalies and global developmental delay with spasticity and/or dystonia. In a multi-center cohort, 25 affected individuals harboring 17 novel pathogenic or likely pathogenic heterozygous RARB variants were reported, and a total of 52 unrelated probands have been described to date, all with de novo or dominant‐segregating variants supporting a primary autosomal dominant inheritance ([PMID:37092537]).

The variant spectrum encompasses missense substitutions clustering in the ligand-binding and DNA-binding domains, as well as nonsense and frameshift changes yielding truncated receptors. A recurrent variant, c.1159C>T (p.Arg387Cys), was observed in multiple unrelated subjects, while additional alleles include frameshift and stop-gain mutations disrupting transcriptional activation or protein stability ([PMID:37092537]).

In vitro transcriptional reporter assays demonstrate that RARB variants can exert either gain-of-function, with enhanced retinoic acid–induced activity, or loss-of-function through a dominant-negative effect likely by impairing ligand binding or coactivator recruitment. These functional classifications correlate with clinical severity and phenotypic variability across the cohort ([PMID:37092537]).

Key site-directed mutagenesis studies have defined critical residues within the ligand-binding pocket; simultaneous mutation of Arg269 and Lys220 to Ala elevates EC₅₀ values for all-trans-RA by 500-fold and confers dominant-negative behavior, confirming mechanistic insights into LOF alleles ([PMID:8034721]). Furthermore, missense changes in the DNA-binding domain impair nuclear localization and transcriptional activity in vitro and partially rescue ocular coloboma in a zebrafish morpholino model, underscoring in vivo relevance ([PMID:31816153]).

Biallelic loss-of-function RARB variants have been reported in a PDAC syndrome featuring microphthalmia and diaphragmatic hernia, illustrating allelic and inheritance‐pattern heterogeneity in RARB-associated disorders ([PMID:24075189]). Nonetheless, the preponderance of de novo dominant variants with concordant functional data affords a robust link between RARB and MCOPS12. Additional large‐scale segregation studies and in vivo models would further refine pathogenic mechanisms.

Key Take-home: Heterozygous RARB variants cause MCOPS12 via gain- or loss-of-function mechanisms, with strong genotype–phenotype correlation and direct translational utility in molecular diagnosis and genetic counseling.

References

• Genetics in Medicine • 2023 • Clinical and functional heterogeneity associated with the disruption of retinoic acid receptor beta. PMID:37092537
• The Journal of Biological Chemistry • 1994 • Arg269 and Lys220 of retinoic acid receptor-beta are important for the binding of retinoic acid. PMID:8034721
• Human Mutation • 2020 • High-throughput custom capture sequencing identifies novel mutations in coloboma-associated genes: Mutation in DNA-binding domain of retinoic acid receptor beta affects nuclear localization causing ocular coloboma. PMID:31816153
• American Journal of Human Genetics • 2013 • Recessive and dominant mutations in retinoic acid receptor beta in cases with microphthalmia and diaphragmatic hernia. PMID:24075189

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