RT Journal Article
SR Electronic
T1 A new seipin-associated neurodegenerative syndrome
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 401
OP 409
DO 10.1136/jmedgenet-2013-101525
VO 50
IS 6
A1 Guillén-Navarro, Encarna
A1 Sánchez-Iglesias, Sofía
A1 Domingo-Jiménez, Rosario
A1 Victoria, Berta
A1 Ruiz-Riquelme, Alejandro
A1 Rábano, Alberto
A1 Loidi, Lourdes
A1 Beiras, Andrés
A1 González-Méndez, Blanca
A1 Ramos, Adriana
A1 López-González, Vanesa
A1 Ballesta-Martínez, María Juliana
A1 Garrido-Pumar, Miguel
A1 Aguiar, Pablo
A1 Ruibal, Alvaro
A1 Requena, Jesús R
A1 Araújo-Vilar, David
YR 2013
UL http://jmg.bmj.com/content/50/6/401.abstract
AB 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.