Molecular analysis and intestinal expression of SAR1 genes and proteins in Anderson's disease (Chylomicron retention disease)

Abstract

BackgroundAnderson'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.MethodsThe 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.ResultsTwo 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.ConclusionsAlthough 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.

Familial cases and male cases with MECP2 mutations

“…The phenotypes of the three female patients were consistent with those of RTT but the five males not. To our knowledge, only about 28 familial cases with MECP2 mutations have been reported (Augenstein et al, 2009; Couvert et al, 2001; Dayer et al, 2007; Evans et al, 2006; Kankirawatanaet al, 2006; Khajuria et al, 2012; Klauck et al, 2002; Lambert et al, 2016; Meloni et al, 2000; Moog et al, 2006; Orrico et al, 2000; Ravn et al, 2011; Villard, 2007; Yntema et al, 2002), with genotypic mutations including missense, frameshift, and nonsense mutations, intragenic deletions and copy number variations (CNV). The phenotypes of those mutation carriers manifested from classical RTT congenital encephalopathy, nonspecific XLMR, and to clinically asymptomatic.…”

“…To our knowledge, anecdotal reports over the past decades accumulated only approximately 28 reports in literature (Augenstein, Lane, Horton, Schanen, & Percy, 2009; Couvert et al, 2001; Dayer et al, 2007; Evans, Archer, Whatley, & Clarke, 2006; Kankirawatana et al, 2006; Khajuria et al, 2012; Klauck et al, 2002; Lambert et al, 2016; Meloni et al, 2000; Moog et al, 2006; Orrico et al, 2000; Ravn et al, 2011; Villard, 2007; Yntema et al, 2002). In this paper, we report Chinese familial cases of eight children and their six mothers with MECP2 mutations, and address their clinical and molecular characteristics and its possibly underlying genetic mechanisms.…”

Insights from human congenital disorders of intestinal lipid metabolism

“…2 ). The obligatory role of Sar1b GTPase is evidenced by the presence of its paralog Sar1a GTPase (216)(217)(218) that is 90% identical, differing by only 20 amino acid residues, but does not compensate for the lack of the Sar1b protein in CRD ( 219 ). Of note, if Sar1a could not compensate for loss of Sar1b in the gut, only limited data are, however, available regarding its contributions in the liver despite the fact that VLDL secretion was not substantially affected in CRD ( 220 ).…”

Overview and Introduction: Thematic Review Series on Intestinal Lipid Metabolism

“…His summary includes a detailed overview of the features and underlying mechanisms contributing to phenotypes in familial hypobetalipoproteinemia and abetalipoproteinemia ( 6 ) as well as a review of chylomicron retention disease (CRD) ( 7 ). Each of these disorders is linked to distinct genes that represent critical points in chylomicron assembly and secretion.…”