Translational control of SEPT9 isoforms is perturbed in disease.

[neuralgic amyotrophy]

A common feature of the mammalian septin gene family is complex genomic architecture with multiple alternate splice variants . Septin 9 has 18 distinct transcripts encoding 15 polypeptides , with two transcripts (SEPT 9 _v 4 and v 4 *) encoding the same polypeptide . We have previously reported that the ratio of these distinct transcripts is altered in neoplasia , with the v 4 transcript being the usual form in normal cells but v 4 * becoming predominant in tumours . This led us to ask what the functional differences between these two transcripts might be . The 5 '-UTRs of v 4 and v 4 * have distinct 5 ' ends encoded by exons 1 beta (v 4 ) and 1 zeta and 2 (v 4 *) and a common 3 ' region and initiating ATG encoded within exon 3 . Here we show that the two mRNAs are translated with different efficiencies and that cellular stress can alter this . A putative internal ribosome entry site can be identified in the common region of the v 4 and v 4 * 5 '-UTRs and translation is modulated by an upstream open -reading frame in the unique region of the v 4 5 '-UTR . Germline mutations in hereditary neuralgic amyotrophy (HNA ) map to the region which is common to the two UTRs . These mutations dramatically enhance the translational efficiency of the v 4 5 '-UTR , leading to elevated SEPT 9 _v 4 protein under hypoxic conditions . Our data provide a mechanistic insight into how the HNA mutations can alter the fine control of SEPT 9 _v 4 protein and its regulation under physiologically relevant conditions and are consistent with the episodic and stress-induced nature of the clinical features of HNA .

Diseases
Validation

Diseases presenting "amyotrophy" symptom

adrenomyeloneuropathy

focal myositis

neuralgic amyotrophy

thoracic outlet syndrome

triple a syndrome

This symptom has already been validated