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 Δ 1 -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.

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

SALVIATI, LEONARDO;
2016

Abstract

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 Δ 1 -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.
2016
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11577/3226221
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