A new seipin-associated neurodegenerative syndrome

J Med Genet. 2013 Jun;50(6):401-9. doi: 10.1136/jmedgenet-2013-101525. Epub 2013 Apr 6.

Abstract

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.

Keywords: Clinical genetics; Epilepsy and seizures; Molecular genetics; Movement disorders (other than Parkinsons); Neurology.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child
  • Exons / genetics
  • Fatal Outcome
  • Female
  • GTP-Binding Protein gamma Subunits / chemistry
  • GTP-Binding Protein gamma Subunits / genetics*
  • GTP-Binding Protein gamma Subunits / metabolism
  • Genotype
  • HeLa Cells
  • Humans
  • Lipodystrophy, Congenital Generalized / genetics*
  • Lipodystrophy, Congenital Generalized / pathology
  • Lipodystrophy, Congenital Generalized / physiopathology
  • Male
  • Mutation*
  • Phenotype
  • RNA Splicing
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • BSCL2 protein, human
  • GTP-Binding Protein gamma Subunits