ORC1 – Meier-Gorlin syndrome

Meier-Gorlin syndrome (MGS) (MONDO:0016817) is an autosomal recessive primordial dwarfism syndrome defined by the clinical triad of microtia, patellar aplasia/hypoplasia, and short stature. Both prenatal and postnatal growth are impaired, often accompanied by microcephaly but preserved cognitive function.

Initial genetic studies identified biallelic ORC1 mutations in multiple MGS families. In a cohort of individuals with absent or hypoplastic patellae, ORC1 variants were found in six unrelated probands (PMID:21358632). A follow-up genotype–phenotype series confirmed autosomal recessive segregation of ORC1 alleles in affected siblings (PMID:22333897).

The ORC1 variant spectrum includes missense, splice-site, and frameshift alleles. Reported changes such as c.314G>A (p.Arg105Gln) and c.1996C>T (p.Arg666Trp) disrupt conserved domains critical for origin recognition and are absent from control datasets.

Functional assays support a loss-of-function mechanism via impaired replication licensing. ORC1 splice variants exhibit defective nuclear translocation and proteasomal regulation in mouse models (PMID:15634681), and yeast complementation of origin licensing factor mutations demonstrates reduced cellular proliferation (PMID:21358631).

Genotype–phenotype correlations indicate that ORC1-mutated individuals display more severe short stature and microcephaly compared with other pre-replication complex gene categories, underscoring gene-specific effects on growth trajectories (PMID:23023959).

Given the definitive genetic and experimental evidence linking ORC1 to MGS, targeted ORC1 sequencing should be integrated into diagnostic panels for primordial dwarfism. ORC1 variant identification informs prognosis and genetic counseling for affected families.

References

• Nature genetics • 2011 • Mutations in the pre-replication complex cause Meier-Gorlin syndrome. PMID:21358632
• European journal of human genetics • 2012 • Meier-Gorlin syndrome genotype-phenotype studies: 35 individuals with pre-replication complex gene mutations and 10 without molecular diagnosis. PMID:22333897
• American journal of medical genetics. Part A • 2012 • Meier-Gorlin syndrome: growth and secondary sexual development of a microcephalic primordial dwarfism disorder. PMID:23023959
• Nature genetics • 2011 • Mutations in origin recognition complex gene ORC4 cause Meier-Gorlin syndrome. PMID:21358631
• The Journal of biological chemistry • 2005 • Novel splicing variant of mouse Orc1 is deficient in nuclear translocation and resistant for proteasome-mediated degradation. PMID:15634681

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