Anderson or chylomicron retention disease: molecular impact of five mutations in the SAR1B gene on the structure and the functionality of Sar1b protein.
Anderson disease (and/or chylomicron retention disease-CMRD) is a rare, autosomic recessive disorder characterized by chronic diarrhea, failure to thrive, and hypocholesterolemia in childhood. The specific molecular defect was identified in 2003 and consists of mutations in the SAR1B gene which encodes for intracellular Sar1b protein. To date, only 8 mutations in six families have been described. We report here 15 new cases of CMRD among 8 families from France and Canada. We identified three unique homozygous mutations of SAR1B gene in French families originated from Turkey, Algeria and Portugal: a stop codon in exon 6 (c.364G>T, p.Glu122X), a whole deletion of exon 2 (c. 1-4482_58+1406 del 5946 ins15bp) and a missense mutation in exon 7 (c.554G>T, p.Gly185Val). The 2 missense mutations found in the 5 French-Canadian families had already been described in the eight previously published mutations: c.409G>A (p.Asp137Asn) and c.537T>A (p.Ser179Arg). In an attempt to explain the functional impairment of mutated proteins, computational analysis and sequence alignment were performed. The nonsense mutation and the whole deletion of exon 2 produced truncated proteins, the missense mutations probably non-functional proteins. All the affected children presented with similar phenotype at onset; the absence of phenotype-genotype correlation was discussed. A determination of the specific mutation in Anderson disease or CMRD is required to ensure diagnosis and allow prompt therapeutic intervention in these children.
Charcosset
Mathilde
M
UF Lipides-Dyslipidémies, Laboratoire de Biochimie, CBE, 59 boulevard Pinel, Bron Cedex, France.
Sassolas
Agnès
A
Peretti
Noël
N
Roy
Claude C
CC
Deslandres
Colette
C
Sinnett
Daniel
D
Levy
Emile
E
Lachaux
Alain
A
D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002914:Chylomicrons / Q000378:metabolism*; D004252:DNA Mutational Analysis; D000795:Fabry Disease / Q000097:blood / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008055:Lipids / Q000097:blood; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020559:Monomeric GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D009154:Mutation; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
D002914:Chylomicrons; D008055:Lipids; C513282:SAR1B protein, human; D020559:Monomeric GTP-Binding Proteins