ORC6 – Meier-Gorlin syndrome

Meier-Gorlin syndrome (MGS) is an autosomal recessive primordial dwarfism disorder characterized by microtia, patellar aplasia or hypoplasia, and short stature. Biallelic variants in ORC6, encoding a subunit of the origin recognition complex essential for DNA replication licensing and cytokinesis, underlie MGS type 3. Patients display a spectrum from mild growth impairment to severe intrauterine lethality with skeletal and craniofacial malformations.

Genetic evidence includes ORC6 mutations identified in at least six unrelated individuals with MGS ([PMID:21358632]), two fetuses with a homozygous frameshift mutation, c.509del (p.Ala170fs) ([PMID:25691413]), and three subjects with compound heterozygous splice-site and start-codon variants, c.449+5G>A and c.2T>C (p.Met1Thr) ([PMID:22333897]). These reports establish autosomal recessive inheritance with biallelic loss-of-function or hypomorphic alleles segregating with disease.

Clinical presentations expand beyond the classic triad to include severe intrauterine growth retardation (HP:0008846), talipes equinovarus (HP:0001762), gracile bones, aplasia/hypoplasia of the patella (HP:0006498), microtia (HP:0008551), and profound short stature (HP:0004322). Phenotypic variability correlates with allele severity; null genotypes often lead to embryonic lethality, whereas hypomorphic alleles yield a survivable, though severe, phenotype.

The ORC6 variant spectrum consists of frameshift (c.509del (p.Ala170fs)), splice-site (c.359+1G>A, c.449+5G>A), nonsense (c.49G>T (p.Glu17Ter)), initiation codon loss (c.2T>C (p.Met1Thr)), and missense (c.695A>C (p.Tyr232Ser)) changes. No recurrent or founder variants have been reported, and carrier frequencies remain undefined.

Functional studies demonstrate that ORC6 loss impairs replication licensing and cytokinesis. A humanized Drosophila model carrying c.67A>G (p.Lys23Glu) shows disrupted DNA binding and ORC assembly ([PMID:33037049]). In vitro minigene assays confirm that c.449+5G>A causes complete exon 4 skipping ([PMID:36012502]), and Drosophila septin complex reconstitution reveals Orc6’s role in filament formation ([PMID:25355953]).

The pathogenic mechanism involves loss of ORC6 function leading to S-phase arrest, apoptosis, and impaired proliferation during embryogenesis and postnatal growth. Hypomorphic alleles partially retain function, accounting for variability in severity. No studies to date refute the ORC6–MGS association.

In summary, strong genetic and moderate functional evidence support a definitive autosomal recessive association between ORC6 and Meier-Gorlin syndrome type 3, guiding molecular diagnosis, genetic counselling, and potential targeted research into replication licensing therapeutics.

Key Take-home: Biallelic ORC6 variants disrupt replication licensing and cytokinesis, causing autosomal recessive Meier-Gorlin syndrome, with strong evidence underpinning clinical testing and counselling.

References

• Nature genetics • 2011 • Mutations in the pre-replication complex cause Meier-Gorlin syndrome. PMID:21358632
• American journal of medical genetics. Part A • 2015 • Further insight into the phenotype associated with a mutation in the ORC6 gene, causing Meier-Gorlin syndrome 3. PMID:25691413
• European journal of human genetics : EJHG • 2012 • Meier-Gorlin syndrome genotype-phenotype studies: 35 individuals with pre-replication complex gene mutations and 10 without molecular diagnosis. PMID:22333897
• Genetics • 2020 • Humanized Drosophila Model of the Meier-Gorlin Syndrome Reveals Conserved and Divergent Features of the Orc6 Protein. PMID:33037049
• International journal of molecular sciences • 2022 • Meier-Gorlin Syndrome: Clinical Misdiagnosis, Genetic Testing and Functional Analysis of ORC6 Mutations and the Development of a Prenatal Test. PMID:36012502
• Molecular biology of the cell • 2015 • Functional insight into the role of Orc6 in septin complex filament formation in Drosophila. PMID:25355953

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