Novel septin 9 repeat motifs altered in neuralgic amyotrophy bind and bundle microtubules.

[neuralgic amyotrophy]

Septin 9 (SEPT 9 ) interacts with microtubules (MTs ) and is mutated in hereditary neuralgic amyotrophy (HNA ), an autosomal-dominant neuropathy . The mechanism of SEPT 9 interaction with MTs and the molecular basis of HNA are unknown . Here , we show that the N-terminal domain of SEPT 9 contains the novel repeat motifs K /R-x-x-E /D and R /K-R-x-E , which bind and bundle MTs by interacting with the acidic C-terminal tails of β-tubulin . Alanine scanning mutagenesis revealed that the K /R-R /x-x-E /D motifs pair electrostatically with one another and the tails of β-tubulin , enabling septin–septin interactions that link MTs together . SEPT 9 isoforms lacking repeat motifs or containing the HNA-linked mutation R 88 W , which maps to the R /K-R-x-E motif , diminished intracellular MT bundling and impaired asymmetric neurite growth in PC -12 cells . Thus , the SEPT 9 repeat motifs bind and bundle MTs , and thereby promote asymmetric neurite growth . These results provide the first insight into the mechanism of septin interaction with MTs and the molecular and cellular basis of HNA .

Diseases
Validation

Diseases presenting "neuropathy" symptom

adrenomyeloneuropathy

dystrophic epidermolysis bullosa

epidermolysis bullosa simplex

erdheim-chester disease

erythropoietic protoporphyria

fabry disease

focal myositis

gm1 gangliosidosis

hirschsprung disease

homocystinuria without methylmalonic aciduria

inclusion body myositis

krabbe disease

malignant atrophic papulosis

megacystis-microcolon-intestinal hypoperistalsis syndrome

neuralgic amyotrophy

oculocutaneous albinism

pendred syndrome

phenylketonuria

pyomyositis

pyruvate dehydrogenase deficiency

sneddon syndrome

thoracic outlet syndrome

triple a syndrome

von hippel-lindau disease

waldenström macroglobulinemia

wolf-hirschhorn syndrome

This symptom has already been validated