CUL7 – 3-M Syndrome

3-M syndrome is an autosomal recessive primordial growth disorder caused by biallelic mutations in the CUL7 gene. The causative role of CUL7 was first mapped to chromosome 6p21.1 and established by identification of 25 distinct mutations in 29 unrelated families (PMID:16142236). Subsequent cohorts have confirmed CUL7 as the major gene, accounting for over three-quarters of molecularly diagnosed cases. Inheritance follows an autosomal recessive pattern with consistent segregation of pathogenic alleles in affected sibships.

Genetic evidence includes reports of homozygous missense, nonsense, splice, and frameshift variants across diverse populations. For example, a homozygous missense mutation c.2975G>C (p.Arg992Pro) was detected in a Japanese patient with maternal uniparental isodisomy (PMID:21166787). A large-scale screen of 33 new cases identified deleterious CUL7 variants in 23 patients, including 19 novel alleles (PMID:19225462). The variant spectrum spans missense, truncating, and splice-site mutations, with occasional founder alleles reported in specific populations.

Affected individuals exhibit severe prenatal and postnatal growth restriction (birth length <–4 SDS), a characteristic triangular face, slender long tubular bones, tall vertebral bodies, and normal intelligence. Additional findings may include inguinal hernia, hip dislocation, scapular winging, and variable skeletal dysplasia. Penetrance is complete for growth failure, and expressivity of dysmorphic features is consistent across cohorts.

Functional studies demonstrate that CUL7 encodes a component of an E3 ubiquitin ligase complex that interacts with Skp1, Fbx29, and ROC1. Pathogenic nonsense (R1445X) and missense (H1464P) mutations abrogate ROC1 recruitment, impair ubiquitination, and disrupt growth signaling (PMID:16142236). Fibroblast assays reveal dysregulated GH-IGF signaling, with altered activation of AKT and MAPK pathways in CUL7-null cells (PMID:23018678).

No studies have refuted the CUL7–3-M syndrome association; while OBSL1 and CCDC8 mutations account for a minority of cases, CUL7 remains the predominant gene, responsible for 77.5% of molecular diagnoses (PMID:21396581). There is no evidence of phenotypic heterogeneity attributable to non-CUL7 alleles that would weaken the gene–disease link.

Integration of genetic and functional data supports a definitive gene-disease relationship. CUL7 testing is recommended for patients with proportionate short stature and characteristic skeletal and facial features. Prenatal diagnosis, preimplantation genetic testing, and targeted management of growth and orthopedic complications are clinically actionable. Key take-home: Biallelic CUL7 mutations cause definitive autosomal recessive 3-M syndrome, with robust genetic and functional evidence informing diagnosis and care.

References

• Nature Genetics • 2005 • Identification of mutations in CUL7 in 3-M syndrome PMID:16142236
• European Journal of Human Genetics • 2009 • A large-scale mutation search reveals genetic heterogeneity in 3M syndrome PMID:19225462
• Clinical Genetics • 2011 • Maternal uniparental isodisomy and heterodisomy on chromosome 6 encompassing a CUL7 gene mutation causing 3M syndrome PMID:21166787
• Journal of Molecular Endocrinology • 2012 • Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling PMID:23018678
• Best Practice & Research Clinical Endocrinology & Metabolism • 2011 • The 3M syndrome PMID:21396581

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