A new seipin-associated neurodegenerative syndrome.


BACKGROUND Seipin/BSCL2 mutations can cause type 2 congenital generalised lipodystrophy (BSCL) or dominant motor neurone diseases. Type 2 BSCL is frequently associated with some degree of intellectual impairment, but not to fatal neurodegeneration. In order to unveil the aetiology and pathogenetic mechanisms of a new neurodegenerative syndrome associated with a novel BSCL2 mutation, six children, four of them showing the BSCL features, were studied. METHODS Mutational and splicing analyses of BSCL2 were performed. The brain of two of these children was examined postmortem. Relative expression of BSCL2 transcripts was analysed by real-time reverse transcription-polymerase chain reaction (RT-PCR) in different tissues of the index case and controls. Overexpressed mutated seipin in HeLa cells was analysed by immunofluorescence and western blotting. RESULTS Two patients carried a novel homozygous c.985C>T mutation, which appeared in the other four patients in compound heterozygosity. Splicing analysis showed that the c.985C>T mutation causes an aberrant splicing site leading to skipping of exon 7. Expression of exon 7-skipping transcripts was very high with respect to that of the non-skipped transcripts in all the analysed tissues of the index case. Neuropathological studies showed severe neurone loss, astrogliosis and intranuclear ubiquitin(+) aggregates in neurones from multiple cortical regions and in the caudate nucleus. CONCLUSIONS Our results suggest that exon 7 skipping in the BSCL2 gene due to the c.985C>T mutation is responsible for a novel early onset, fatal neurodegenerative syndrome involving cerebral cortex and basal ganglia.

DOI: 10.1136/jmedgenet-2013-101525

Cite this paper

@article{GuillnNavarro2013ANS, title={A new seipin-associated neurodegenerative syndrome.}, author={Encarna Guill{\'e}n-Navarro and Sof{\'i}a S{\'a}nchez-Iglesias and Rosario Domingo-Jim{\'e}nez and Berta Victoria and Alejandro Ruiz-Riquelme and Alberto R{\'a}bano and Lourdes Loidi and A Beiras and Blanca Gonz{\'a}lez-M{\'e}ndez and Adriana Ramos and Vanesa L{\'o}pez-Gonz{\'a}lez and Mar{\'i}a Juliana Ballesta-Mart{\'i}nez and Miguel Garrido-Pumar and Pablo Aguiar and {\'A}lvaro Ruibal and Jes{\'u}s R Requena and David Ara{\'u}jo-Vilar}, journal={Journal of medical genetics}, year={2013}, volume={50 6}, pages={401-9} }