SAR1B – Chylomicron Retention Disease

The association between SAR1B and chylomicron retention disease is supported by a robust body of evidence, spanning multiple independent case reports and multi‐patient studies. This lipid malabsorption disorder is characterized by clinical features such as failure to thrive, steatorrhea, and fat malabsorption. The condition follows an autosomal recessive inheritance pattern, and patients frequently present in infancy with symptoms that prompt early diagnostic evaluation (PMID:19846172). Detailed molecular analysis has revealed that mutations in SAR1B disrupt chylomicron secretion, leading to cytosolic lipid accumulation in enterocytes.

Genetic investigations across diverse populations have identified homozygous and compound heterozygous mutations in SAR1B. Several independent studies report consistent findings with patients harboring loss‐of‐function variants. One key mutation described is c.83_84del (p.Leu28fs), which has been reported in distinct ethnic groups and is representative of the mutational spectrum observed (PMID:29713611). Genetic evidence is further strengthened by the recurrence of similar variants observed in unrelated families, confirming the pathogenic role of SAR1B in this disorder.

Although segregation data are modest—with no extensive reports of multiple affected relatives beyond the probands—the familial studies in consanguineous groups offer supportive, albeit limited, segregation evidence (PMID:32257723). In some instances, variable phenotypic expression has been noted within families, underscoring the complexity of genotype-phenotype correlations in chylomicron retention disease.

Functional studies have provided critical insight into the disease mechanism. In vitro experiments, including cellular knockdown models, have demonstrated that disruption of SAR1B impairs chylomicron secretion, leading to marked triglyceride and apolipoprotein B-48 reduction (PMID:28982670). Moreover, protein truncation and misfolding resulting from frameshift and nonsense variants have been shown to be concordant with the clinical phenotype observed in patients (PMID:17945526).

The integrated evidence from genetic and functional studies strongly supports a causal relationship between pathogenic variants in SAR1B and chylomicron retention disease. Multiple independent studies have consistently identified deleterious mutations, and experimental data confirm that loss-of-function of SAR1B disrupts normal lipid processing. While some phenotypic variability exists, the overall data highlight a clear diagnostic utility for genetic testing of SAR1B in suspected cases.

Key take‑home: The strong association between SAR1B mutations and chylomicron retention disease validates its role as a critical diagnostic marker and supports its clinical application for early diagnosis and appropriate management of affected individuals.

References

• Metabolism: clinical and experimental • 2010 • Variable phenotypic expression of chylomicron retention disease in a kindred carrying a mutation of the Sara2 gene PMID:19846172
• Pediatric gastroenterology, hepatology & nutrition • 2018 • Chylomicron Retention Disease: a Description of a New Mutation in a Very Rare Disease PMID:29713611
• Cureus • 2020 • Chylomicron Retention Disease in A Male Infant: A Rare Case from Pakistan PMID:32257723
• Clinical genetics • 2008 • Anderson's disease (chylomicron retention disease): a new mutation in the SARA2 gene associated with muscular and cardiac abnormalities PMID:18786134
• Molecular genetics and metabolism • 2008 • Anderson or chylomicron retention disease: molecular impact of five mutations in the SAR1B gene on the structure and the functionality of Sar1b protein PMID:17945526
• Arteriosclerosis, thrombosis, and vascular biology • 2017 • Understanding Chylomicron Retention Disease Through Sar1b Gtpase Gene Disruption: Insight From Cell Culture PMID:28982670
• The Journal of biological chemistry • 2012 • The SEC23-SEC31 interface plays critical role for export of procollagen from the endoplasmic reticulum PMID:22298774

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