The gene AKR1D1 has been definitively associated with the disease Congenital Bile Acid Synthesis Defect 2 according to the gene–disease association criteria of the ACMG (SOP version 11). This disease results from an anomaly of bile acid synthesis and is characterized by severe and rapidly progressive cholestatic liver disease, and malabsorption of fat and fat-soluble vitamins. Homozygous or compound heterozygous mutations in the AKR1D1 gene cause this disease.
Mutations in AKR1D1 cause congenital bile acid synthesis defect type 2 by impairing the enzyme 3-oxo-5-β-steroid 4-dehydrogenase. This enzyme, crucial for bile acid production, is responsible for the NADPH-dependent conversion of 5beta-cholestan-3-one to cholest-4-en-3-one. Impaired conversion leads to abnormal bile acids, cholesterol buildup, and fat-soluble vitamin deficiencies (PMID: 30809085). The AKR1D1 enzyme's biochemical disruptions were initially identified using FAB-MS, revealing high 3-oxo-Δ4 bile acids and low normal bile acid conjugates in urine (PMID: 1735522). Affected infants present with symptoms of jaundice, failure to thrive, and steatorrhea. Timely diagnosis is vital because the liver disease associated with this condition can be life-threatening (it can lead to cirrhosis and death), yet it can be managed with oral primary bile acid replacement (PMID: 30809085).
Summary of Case Level Data (10.2 points): 10 probands were scored with 7 variants (2 frameshift, 1 nonsense, 5 missense) from 4 publications (PMID: 23679950, 35758383, 12970144, 23323017).
Summary of Experimental Evidence (2.5 points): AKR1D1 knockout mice indicated sex-specific metabolic alterations. Male knockout mice had enhanced insulin sensitivity and decreased lipid buildup in the liver and adipose tissue, but had higher triglyceride levels and intramuscular triacylglycerol. These findings underline AKR1D1's important function in regulating bile acid synthesis and metabolic balance in a sex-specific way. (PMID: 35318963). Another study characterized AKR1D1 mutations. Clinically relevant mutants showed reduced activity, decreased stability, and heightened thermolability. One mutant (P133R) exhibited uncompetitive kinetics and lower catalytic efficiency, compromising bile acid synthesis and leading to potential bile acid deficiency syndromes
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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