Exploiting in silico structural analysis to introduce emerging genotype–phenotype correlations in DHCR24-related sterol biosynthesis disorder: a case study

Desmosterolosis is a rare sterol biosynthesis disorder characterized by multiplecongenital anomalies, failure to thrive, severe developmental delay, progressiveepileptic encephalopathy, and elevated levels of desmosterol caused by biallelicmutations of DHCR24 encoding 3-β-hydroxysterol Δ-24-reductase. DHCR24 isregarded as the key enzyme of cholesterol synthesis in the metabolism of braincholesterol as it catalyzes the reduction of the Δ-24 double bond of sterolintermediates during cholesterol biosynthesis. To date, 15 DHCR24 variants,detected in 2 related and 14 unrelated patients, have been associated with thedesmosterolosis disorder. Here, we describe a proband harboring the never-described DHCR24 homozygous missense variant NM_014762.4:c.506T>C, NP_055577.1:p.M169T, whose functional validation was confirmed throughbiochemical assay. By using molecular dynamics simulation techniques, weinvestigated the impact of this variant on the protein stability and interactionnetwork with the flavin adenine dinucleotide cofactor, thereby providing apreliminary assessment of its mechanistic role in comparison to all knownpathogenic variants, the wild-type protein, and a known benign DHCR24variant. This report expands the clinical and molecular spectra of the DHCR24-related disorder, reports on a novel DHCR24 deleterious variant associated withdesmosterolosis, and gives new insights into genotype–phenotype correlations.