title: Molecular analysis and intestinal expression of SAR1 genes and proteins in Anderson's disease (Chylomicron retention disease).
abstract: BACKGROUND
  Anderson's disease (AD) or chylomicron retention disease (CMRD) is a very rare hereditary lipid malabsorption syndrome. In order to discover novel mutations in the SAR1B gene and to evaluate the expression, as compared to healthy subjects, of the Sar1 gene and protein paralogues in the intestine, we investigated three previously undescribed individuals with the disease.
  
  
  METHODS
  The SAR1B, SAR1A and PCSK9 genes were sequenced. The expression of the SAR1B and SAR1A genes in intestinal biopsies of both normal individuals and patients was measured by RTqPCR. Immunohistochemistry using antibodies to recombinant Sar1 protein was used to evaluate the expression and localization of the Sar1 paralogues in the duodenal biopsies.
  
  
  RESULTS
  Two patients had a novel SAR1B mutation (p.Asp48ThrfsX17). The third patient, who had a previously described SAR1B mutation (p.Leu28ArgfsX7), also had a p.Leu21dup variant of the PCSK9 gene. The expression of the SAR1B gene in duodenal biopsies from an AD/CMRD patient was significantly decreased whereas the expression of the SAR1A gene was significantly increased, as compared to healthy individuals. The Sar1 proteins were present in decreased amounts in enterocytes in duodenal biopsies from the patients as compared to those from healthy subjects.
  
  
  CONCLUSIONS
  Although the proteins encoded by the SAR1A and SAR1B genes are 90% identical, the increased expression of the SAR1A gene in AD/CMRD does not appear to compensate for the lack of the SAR1B protein. The PCSK9 variant, although reported to be associated with low levels of cholesterol, does not appear to exert any additional effect in this patient. The results provide further insight into the tissue-specific nature of AD/CMRD.
authors.affiliation: INSERM U781, Université Paris Descartes, Hôpital Necker Enfants Malades, Paris, 75015, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Georges
authors.forename: Jessica
authors.initials: J
authors.lastname: Bonneau
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonnefont-Rousselot
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Champigneulle
authors.forename: Jean P
authors.initials: JP
authors.lastname: Rabès
authors.forename: Marianne
authors.initials: M
authors.lastname: Abifadel
authors.forename: Thomas
authors.initials: T
authors.lastname: Aparicio
authors.forename: Jean C
authors.initials: JC
authors.lastname: Guenedet
authors.forename: Eric
authors.initials: E
authors.lastname: Bruckert
authors.forename: Catherine
authors.initials: C
authors.lastname: Boileau
authors.forename: Alain
authors.initials: A
authors.lastname: Morali
authors.forename: Mathilde
authors.initials: M
authors.lastname: Varret
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Aggerbeck
authors.forename: Marie E
authors.initials: ME
authors.lastname: Samson-Bouma
mesh_terms: D000293:Adolescent; D002648:Child; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D006995:Hypobetalipoproteinemias / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism*; D008286:Malabsorption Syndromes / Q000235:genetics / Q000378:metabolism; D008297:Male; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases / Q000235:genetics
chemical_list: C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C493083:SAR1A protein, human; C513282:SAR1B protein, human; D020559:Monomeric GTP-Binding Proteins