These authors contributed equally to this work.
Novel splice-site mutations and a large intragenic deletion in PLA2G6 associated with a severe and rapidly progressive form of infantile neuroaxonal dystrophy
Version of Record online: 27 FEB 2010
© 2010 John Wiley & Sons A/S
Volume 78, Issue 5, pages 432–440, November 2010
How to Cite
Tonelli, A., Romaniello, R., Grasso, R., Cavallini, A., Righini, A., Bresolin, N., Borgatti, R. and Bassi, M. (2010), Novel splice-site mutations and a large intragenic deletion in PLA2G6 associated with a severe and rapidly progressive form of infantile neuroaxonal dystrophy. Clinical Genetics, 78: 432–440. doi: 10.1111/j.1399-0004.2010.01417.x
- Issue online: 27 FEB 2010
- Version of Record online: 27 FEB 2010
- Received 9 December 2009, revised and accepted for publication 22 February 2010
- intragenic deletion;
Tonelli A, Romaniello R, Grasso R, Cavallini A, Righini A, Bresolin N, Borgatti R, Bassi MT. Novel splice-site mutations and a large intragenic deletion in PLA2G6 associated with a severe and rapidly progressive form of infantile neuroaxonal dystrophy.
Infantile neuroaxonal dystrophy, INAD, is a severe progressive psychomotor disorder with infantile onset and characterized by the presence of axonal spheroids throughout the central and peripheral nervous systems. A subset of INAD patients shows also brain iron accumulation which represents instead the distinctive feature of the idiopathic neurodegeneration with brain iron accumulation, NBIA. These diseases share the same causative gene, PLA2G6, encoding iPLA2-VIA, a calcium-independent phospholipase. Mutations that lead to a complete absence of protein are associated with a severe INAD profile, while compound heterozygous mutations with possibly a residual protein activity are instead associated with the less severe NBIA phenotype. Here we describe two INAD patients both with an unusually rapid disease progression and a peculiar neuroradiological presentation in one of them. Compound heterozygosity for a large intragenic deletion and a nonsense mutation was found in one of them while the other is carrying two novel splice-site mutations. Breakpoint-sequence analysis suggests a non-allelic-homologous-recombination (NAHR) event, probably underlying the rearrangement. These findings, while supporting the genotype–phenotype correlation already observed in INAD patients, provide the first sequence characterization of a genomic rearrangement in PLA2G6 gene, thus orienting the search for missing mutant alleles in PLA2G6 related diseases.