TY - JOUR
T1 - A new seipin-associated neurodegenerative syndrome
AU - Guillén-Navarro, Encarna
AU - Sánchez-Iglesias, Sofía
AU - Domingo-Jiménez, Rosario
AU - Victoria, Berta
AU - Ruiz-Riquelme, Alejandro
AU - Rábano, Alberto
AU - Loidi, Lourdes
AU - Beiras, Andrés
AU - González-Méndez, Blanca
AU - Ramos, Adriana
AU - López-González, Vanesa
AU - Ballesta-Martínez, María Juliana
AU - Garrido-Pumar, Miguel
AU - Aguiar, Pablo
AU - Ruibal, Alvaro
AU - Requena, Jesús R.
AU - Araújo-Vilar, David
N1 - Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 2013
Y1 - 2013
N2 - 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.
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.
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U2 - 10.1136/jmedgenet-2013-101525
DO - 10.1136/jmedgenet-2013-101525
M3 - Article
C2 - 23564749
AN - SCOPUS:84878858814
SN - 0022-2593
VL - 50
SP - 401
EP - 409
JO - Journal of medical genetics
JF - Journal of medical genetics
IS - 6
ER -