Novel missense mutation in ALS2 gene results in infantile ascending hereditary spastic paralysis

Abstract

These results highlight the important role of the RCC1-like domain in ALS2 stability and function that is essential for upper motor neuron maintenance.

Screening of ARHSP-TCC patients expands the spectrum ofSPG11mutations and includes a large scale gene deletion

“…The practical consequence of the large number of different mutations identified, in terms of the diagnosis of ARHSP-TCC, is that a quick, DNAbased test seems unfeasible. We can speculate that a protein-based diagnostic assay of the type being developed in other forms of spinocerebellar degenerations [i.e., ALS2 (Eymard-Pierre et al 2006), ataxia-telangectasia syndrome (Sutton at al. 2004) or ataxia with oculomotor apraxia type 1 (Ferrarini et al 2007)] will be more effective.…”

Advantages and Pitfalls in Experimental Models Of ALS

“…Therefore, loss of ALS2 may perturb macropinocytosis and/or the following membrane trafficking, which gives rise to neuronal dysfunction in the ALS2-linked MN diseases (Devon et al, 2006;Kunita et al, 2007). In fact, ALS2 loss of function mutations in humans account for several juvenile recessive MN diseases: the juvenile ALS, the primary lateral sclerosis and the infantile-onset ascending hereditary spastic paralysis (Eymard-Pierre et al, 2006;Orban et al, 2007). Furthermore, alsin plays a role in AMPA receptor trafficking, thus providing a novel pathogenic link between ALS2-deficiency and MN degeneration, suggesting a protective role in maintaining the survival of MNs (Lai et al, 2006).…”

Alsin and the Molecular Pathways of Amyotrophic Lateral Sclerosis

“…To date, at least 12 different mutations in the 34 exons spanning the ALS2 gene have been described in African and Asian families with juvenile ALS and PLS and in European and Asian families with hereditary spastic paralysis (see Table 1). With the exception of two recently identified homozygous missense mutations at the amino terminal [7,8], the majority of the mutations appear to result in the generation of a premature stop codon, resulting in protein instability and a loss of function [9]. The relationship between the missense mutations and alsin function is unclear.…”

“…Of the reported mutations to date, only four (261delA, 553delA, G660A, and 1130delAT) are found in the RCC1 domain region expected to affect both forms of the protein, and of these, the two nearest to the amino-terminus (261delA and 553delA) result in frame shift mutations that are responsible for the development of juvenile ALS (ALS2) [5,6,10]. The other two mutations that keep most of the short form of alsin intact primarily affect upper motor neurons [8,11]. This observation has led to speculation that an intact short form of alsin may protect lower motor neurons and be responsible for the varying severity of clinical phenotypes [6].…”

“…Distribution of transfected full-length alsin protein is primarily cytosolic, with only a small minority localizing to vesicular-like structures [9,14,16]. These alsin-positive structures appear to be early endosomal as several groups have reported co-localization of alsin with the early endosome antigen 1 (EEA1) and Rab5 [8,11]. Rab GTPases typically regulate intracellular protein and membrane trafficking events, and three isoforms of Rab5 exist in mammalian systems: Rab5a, Rab5b, and Rab5c [20].…”