J Med Genet doi:10.1136/jmedgenet-2013-101525
  • Genotype-phenotype correlations
  • Original article

A new seipin-associated neurodegenerative syndrome

  1. David Araújo-Vilar2
  1. 1Unit of Medical Genetics and Dysmorphology, Division of Pediatrics, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
  2. 2Department of Medicine, School of Medicine and CIMUS Biomedical Research Institute, University of Santiago de Compostela-IDIS, Santiago de Compostela, Spain
  3. 3Section of Neuropediatrics, Division of Pediatrics, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
  4. 4Neuropathology Department and Tissue Bank, Fundación CIEN, Madrid, Spain
  5. 5Fundación Galega de Medicina Xenómica, Santiago de Compostela, Spain
  6. 6Department of Pathology, School of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain
  7. 7Division of Nuclear Medicine, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain
  1. Correspondence to Dr David Araújo-Vilar, Department of Medicine-IDIS, CIMUS-Facultade de Medicina, University of Santiago de Compostela, Avda de Barcelona s/n, Santiago de Compostela 15707, Spain; david.araujo{at}
  • Received 9 January 2013
  • Revised 10 March 2013
  • Accepted 11 March 2013
  • Published Online First 6 April 2013


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.