title: A new seipin-associated neurodegenerative syndrome.
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.
authors.affiliation: Unit of Medical Genetics and Dysmorphology, Division of Pediatrics, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain.
authors.forename: Encarna
authors.initials: E
authors.lastname: Guillén-Navarro
authors.forename: Sofía
authors.initials: S
authors.lastname: Sánchez-Iglesias
authors.forename: Rosario
authors.initials: R
authors.lastname: Domingo-Jiménez
authors.forename: Berta
authors.initials: B
authors.lastname: Victoria
authors.forename: Alejandro
authors.initials: A
authors.lastname: Ruiz-Riquelme
authors.forename: Alberto
authors.initials: A
authors.lastname: Rábano
authors.forename: Lourdes
authors.initials: L
authors.lastname: Loidi
authors.forename: Andrés
authors.initials: A
authors.lastname: Beiras
authors.forename: Blanca
authors.initials: B
authors.lastname: González-Méndez
authors.forename: Adriana
authors.initials: A
authors.lastname: Ramos
authors.forename: Vanesa
authors.initials: V
authors.lastname: López-González
authors.forename: María Juliana
authors.initials: MJ
authors.lastname: Ballesta-Martínez
authors.forename: Miguel
authors.initials: M
authors.lastname: Garrido-Pumar
authors.forename: Pablo
authors.initials: P
authors.lastname: Aguiar
authors.forename: Alvaro
authors.initials: A
authors.lastname: Ruibal
authors.forename: Jesús R
authors.initials: JR
authors.lastname: Requena
authors.forename: David
authors.initials: D
authors.lastname: Araújo-Vilar
mesh_terms: D002648:Child; D005091:Exons / Q000235:genetics; D017809:Fatal Outcome; D005260:Female; D044388:GTP-Binding Protein gamma Subunits / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D052497:Lipodystrophy, Congenital Generalized / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009154:Mutation; D010641:Phenotype; D012326:RNA Splicing; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C432679:BSCL2 protein, human; D044388:GTP-Binding Protein gamma Subunits
keywords: Clinical genetics; Epilepsy and seizures; Molecular genetics; Movement disorders (other than Parkinsons); Neurology