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ALDH18A1 gene mutations cause dominant spastic paraplegia SPG9: loss of function effect and plausibility of a dominant negative mechanism

2015; Oxford University Press; Volume: 139; Issue: 1 Linguagem: Inglês

10.1093/brain/awv247

1460-2156

Emanuele Panza, Juan Manuel Escamilla, Clara Marco‐Marín, Nadine Gougeard, Giuseppe De Michele, Vincenzo Brescia Morra, Rocco Liguori, Leonardo Salviati, Maria Alice Donati, Roberto Cusano, Tommaso Pippucci, Roberto Ravazzolo, Andrea H. Németh, Sarah Smithson, Sally Davies, Jane A. Hurst, Domenico Bordo, Vicente Rubio, Marco Seri,

Endoplasmic Reticulum Stress and Disease

Sir, We have read with great interest the article published recently in Brain by Coutelier et al. (2015) ‘Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia’. In support of the message of this paper, we would like to report that mutations in ALDH18A1 , the causative gene in Coutelier’s paper, are the cause of SPG9 (MIM#601162), a rare form of autosomal dominant hereditary spastic paraplegia (HSP) complicated with vomiting and congenital bilateral cataracts that was reported by our group in a British family and an Italian family (Slavotinek et al. , 1996; Seri et al. , 1999). The British family that we report presents one of the dominant mutations reported by Coutelier et al. (2015). Furthermore, we show that the mutations we report here are loss-of-function mutations by using site-directed mutagenesis and enzyme activity studies with purified recombinant Δ1-pyrroline-5-carboxylate synthetase (P5CS), the enzyme encoded by ALDH18A1 . Finally, we provide some experimental and structural evidence that renders plausible a dominant negative mechanism for the dominant inheritance of the disease for these mutations and for other ALDH18A1 mutations exhibiting this type of inheritance. We searched for mutations in ALDH18A1 in the two SPG9 families because this gene is located within the SPG9-linked region of 10q23.3-q24.2 (Seri et al. , 1999), not having been discarded as a candidate gene by rounds of fine positional mapping and gene exclusion within this 4.78 Mb region (Lo Nigro et al. , 2000; Panza et al. , 2008). Furthermore, we focused on ALDH18A1 because its mutations were known to cause a condition (MIM#219150) presenting some phenotypic resemblance with SPG9, including a neurodevelopmental syndrome with cataracts and recurrent vomiting (Baumgartner et al. , 2000, 2005; Bicknell et al. , 2008; Skidmore et al. , 2011 …