Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling

Area of Science:

• Genetics and Molecular Biology
• Endocrinology
• Pediatric Growth Disorders

Background:

• 3-M syndrome is a rare primordial growth disorder linked to mutations in CUL7, OBSL1, and CCDC8 genes.
• Patients with 3-M syndrome exhibit a limited response to growth hormone (GH) treatment, but the underlying mechanisms remain unclear.

Purpose of the Study:

• To identify mutations in 13 families with 3-M syndrome.
• To characterize the GH-IGF axis in children with 3-M syndrome.
• To investigate GH and IGF1 signaling in patient-derived fibroblast cell lines.

Main Methods:

• Genetic screening of 13 3-M syndrome families for CUL7, OBSL1, and CCDC8 mutations.
• Assay of GH and IGF1 levels in 3-M patients.
• Analysis of GH and IGF1 signaling pathways (STAT5b, MAPK, AKT) in patient-derived fibroblast cell lines.

Main Results:

• Mutations were identified in CUL7 (11 families), OBSL1 (3 families), and CCDC8 (1 family). CUL7 mutations correlated with shorter stature.
• Most patients had normal GH and normal/low IGF1 levels, suggesting potential GH/IGF1 resistance.
• Impaired GH signaling was observed in OBSL1(-/-) and CCDC8(-/-) cells, while IGF1 signaling was reduced in CUL7(-/-) and OBSL1(-/-) cells.

Conclusions:

• The study identified the prevalence of mutations in CUL7 (69%), OBSL1 (23%), and CCDC8 (8%) in 3-M syndrome.
• Dysregulation of the GH-IGF-IGF binding protein axis contributes to the growth impairment seen in 3-M syndrome.
• Impaired signaling pathways provide a molecular basis for the GH/IGF1 resistance observed in 3-M syndrome patients.