SEPTIN9 – Hereditary Neuralgic Amyotrophy

Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant disorder characterized by recurrent, painful, unilateral neuropathy of the upper brachial plexus leading to muscle weakness and wasting. The condition may include minor dysmorphisms such as hypotelorism and cleft palate. HNA is linked to mutations in SEPTIN9, which encodes a septin family GTP-binding protein essential for cytoskeletal organization (PMID:31619932).

Genetic studies have identified four unrelated probands (three from two familial HNA pedigrees and one isolated case) with heterozygous missense variants in SEPTIN9 (PMID:17546647; PMID:31619932). Segregation in two multiplex families confirms autosomal dominant inheritance with at least two additional affected relatives. The pathogenic spectrum comprises three missense changes: c.262C>T (p.Arg88Trp), c.278C>T (p.Ser93Phe), and c.316C>T (p.Arg106Trp) (PMID:17546647).

No loss-of-function or splice variants have been reported in HNA; all disease-causing alleles to date are missense. The recurrence of distinct variants in unrelated families and absence from population databases support pathogenicity under ACMG guidelines.

Functional assays demonstrate that HNA-associated variants disrupt normal septin filament dynamics and protein interactions. In mammalian cells, p.Arg88Trp and p.Ser93Phe exhibit aberrant co-assembly with SEPT4/SEPT11 and resistance to Rho/Rhotekin signaling (PMID:17546647). The p.Arg88Trp (R88W) mutant also impairs microtubule bundling and asymmetric neurite extension in neuronal model cells, implicating a dominant-negative mechanism (PMID:24344182).

There is no conflicting evidence disputing the SEPTIN9–HNA link. Additional expression and overexpression studies in neoplasia lie outside the primary neuropathic context but underscore SEPT9’s role in cytoskeletal regulation.

Together, genetic segregation and detailed functional characterization establish a strong gene–disease association between SEPTIN9 and HNA. Genetic screening for SEPTIN9 missense variants provides a critical diagnostic tool for patients with recurrent brachial plexus neuropathy.

References

• Turk pediatri arsivi • 2019 • A rare cause of brachial plexopathy: hereditary neuralgic amyotrophy. PMID:31619932
• Human mutation • 2007 • SEPT9 sequence alternations causing hereditary neuralgic amyotrophy are associated with altered interactions with SEPT4/SEPT11 and resistance to Rho/Rhotekin-signaling. PMID:17546647
• The Journal of cell biology • 2013 • Novel septin 9 repeat motifs altered in neuralgic amyotrophy bind and bundle microtubules. PMID:24344182

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