OBSL1 – 3-M syndrome

3-M syndrome is a rare autosomal recessive primordial growth disorder characterized by severe pre- and postnatal growth retardation, characteristic facial dysmorphism, tall vertebral bodies, and normal intelligence. Pathogenic variants in CUL7, OBSL1, or CCDC8 disrupt ubiquitination and cytoskeletal scaffolding, leading to impaired growth factor signalling and skeletal development (PMID:21396581). OBSL1 encodes a putative cytoskeletal adaptor that localizes to the nuclear envelope and modulates CUL7 stability, placing it within a shared molecular pathway underpinning 3-M syndrome.

Biallelic OBSL1 variants have been reported in 13 unrelated families (n = 21 probands) encompassing nonsense, frameshift, and splice mutations, consistent with loss-of-function as the disease mechanism (PMID:19481195, PMID:34597859). The variant spectrum includes recurrent deep-intronic and coding changes such as c.458dupG (p.Leu154ProfsTer100) observed in five Chinese patients, suggesting a population-specific hotspot (PMID:38407006).

Several case reports illustrate phenotypic variability and therapeutic response. Two Korean siblings with OBSL1 compound heterozygous mutations, c.3341G>A (p.Trp1114Ter) and c.2135-3_2135-2del, presented with short stature (–3.4 SDS), advanced bone age, and subtle dysmorphic features; combined GH and GnRH agonist therapy yielded height gains despite presumed GH resistance (PMID:33107243). A Chinese girl with c.458dupG (p.Leu154ProfsTer100) and c.427dupG (p.Ala143GlyfsTer111) exhibited low birth weight and intrauterine growth retardation, reinforcing the clinical utility of OBSL1 genetic testing in early-onset short stature (PMID:38407006).

Segregation analysis is limited but includes affected siblings in multiple reports (e.g., two Korean siblings) and homozygous cases in consanguineous families; overall, at least two additional affected relatives have been documented, confirming recessive inheritance. OBSL1 variants co-segregate with 3-M phenotype in sibships, supporting pathogenicity.

Functional studies in patient fibroblasts demonstrate that OBSL1 loss leads to downregulation of CUL7 protein, dysregulated IGFBP2/IGFBP5 expression, and impaired STAT5B/MAPK and AKT activation in response to GH and IGF1, consistent with a combined GH and IGF1 resistance mechanism (PMID:19877176, PMID:23018678). These assays provide moderate evidence of pathogenic mechanism concordant with human phenotype.

Together, genetic and experimental data support a Strong clinical validity classification for OBSL1-related 3-M syndrome, with robust genetic evidence for biallelic loss-of-function variants and concordant mechanistic studies. OBSL1 testing should be considered in patients with prenatal growth restriction, characteristic facial and skeletal features, and short stature. Key take-home: OBSL1 biallelic loss-of-function variants cause autosomal recessive 3-M syndrome via haploinsufficiency, warranting genetic confirmation for diagnosis and management.

References

• Best practice & research. Clinical endocrinology & metabolism • 2011 • 3M syndrome: molecular and clinical overview PMID:21396581
• American Journal of Human Genetics • 2009 • The primordial growth disorder 3-M syndrome connects ubiquitination to the cytoskeletal adaptor OBSL1 PMID:19481195
• Human Mutation • 2010 • OBSL1 mutations in 3-M syndrome are associated with a modulation of IGFBP2 and IGFBP5 expression levels PMID:19877176
• Journal of Molecular Endocrinology • 2012 • Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling PMID:23018678
• European Journal of Medical Genetics • 2021 • Natural history of facial and skeletal features from neonatal period to adulthood in a 3-M syndrome cohort with biallelic CUL7 or OBSL1 variants PMID:34597859
• Yonsei Medical Journal • 2020 • The Effect of Combined Growth Hormone and a Gonadotropin-Releasing Hormone Agonist Therapy on Height in Korean 3-M Syndrome Siblings PMID:33107243
• Journal of Clinical Research in Pediatric Endocrinology • 2024 • Novel OBSL1 Variant in a Chinese Patient with 3M Syndrome: The c.458dupG Mutation May Be a Potential Hotspot Mutation in the Chinese Population PMID:38407006

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