NOG – Multiple Synostoses Syndrome 1

Multiple synostoses syndrome 1 (SYNS1) is an autosomal dominant skeletal disorder characterized by progressive fusion of joints, most notably in the hands and feet, often accompanied by conductive hearing impairment due to stapes ankylosis. The disease is caused by heterozygous mutations in NOG (noggin), which encodes a secreted antagonist of bone morphogenetic proteins (BMPs) critical for joint development and maintenance (Gene Symbol, Disease Name).

Genetic evidence supports a strong gene–disease association: three unrelated families harbor distinct missense variants affecting conserved cysteine residues in NOG. A Japanese pedigree presented with c.682T>G (p.Cys228Gly) co-segregating with stapes ankylosis and broad digits (PMID:26211601). A Danish family with SYNS1 exhibited a novel c.689G>A (p.Cys230Tyr) variant and proximal symphalangism without hearing loss (PMID:26994744). A Chinese three-generation family carried c.533G>A (p.Cys178Tyr) segregating in six affected individuals (PMID:35332702).

Segregation analysis demonstrated co-segregation in at least five additional affected relatives across these pedigrees, underscoring autosomal dominant inheritance with high penetrance (PMID:26211601; PMID:26994744; PMID:35332702).

Functional assays reveal a hypomorphic mechanism: a SYNS1-associated NOG missense allele abolished secretion of noggin dimers in COS-7 cells, while other missense variants reduced secretion efficiency (PMID:11562478). A separate study showed that the p.Trp150Cys mutation interferes with noggin dimerization in patient leukocytes (PMID:25888563). These data indicate that impaired noggin secretion or dimer formation leads to insufficient BMP antagonism and joint fusion.

No conflicting evidence has been reported for NOG in SYNS1, and experimental findings are concordant across models. Additional rare NOG variants have been described in related symphalangism spectrum disorders, but the core association with SYNS1 is well supported.

In conclusion, heterozygous NOG mutations cause autosomal dominant multiple synostoses syndrome 1 via a loss-of-function mechanism affecting BMP regulation. Genetic testing for NOG should be considered in individuals with joint fusions and conductive hearing loss. Key Take-home: NOG variants disrupting cysteine‐mediated dimerization are a clinically actionable cause of SYNS1.

References

• European journal of medical genetics • 2015 • Novel NOG mutation in Japanese patients with stapes ankylosis with broad thumbs and toes PMID:26211601
• American journal of medical genetics. Part A • 2016 • Further delineation of facioaudiosymphalangism syndrome: Description of a family with a novel NOG mutation and without hearing loss. PMID:26994744
• Molecular genetics & genomic medicine • 2022 • Clinical observation and genetic analysis of a SYNS1 family caused by novel NOG gene mutation. PMID:35332702
• Proceedings of the National Academy of Sciences of the United States of America • 2001 • Human disease-causing NOG missense mutations: effects on noggin secretion, dimer formation, and bone morphogenetic protein binding. PMID:11562478
• The Annals of otology, rhinology, and laryngology • 2015 • A Novel Missense Mutation of NOG Interferes With the Dimerization of NOG and Causes Proximal Symphalangism Syndrome in a Chinese Family. PMID:25888563

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