Lathosterolosis: an inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency

Abstract

Lathosterol 5-desaturase catalyzes the conversion of lathosterol to 7-dehydrocholesterol in the next to last step of cholesterol synthesis. Inborn errors of cholesterol synthesis underlie a group of human malformation syndromes including Smith-Lemli-Opitz syndrome, desmosterolosis, CHILD syndrome, CDPX2 and lathosterolosis. We disrupted the lathosterol 5-desaturase gene (Sc5d ) in order to further our understanding of the pathophysiological processes underlying these disorders and to gain insight into the corresponding human disorder. Sc5d (-/-) pups were stillborn, had elevated lathosterol and decreased cholesterol levels, had craniofacial defects including cleft palate and micrognathia, and limb patterning defects. Many of the malformations found in Sc5d (-/-) mice are consistent with impaired hedgehog signaling, and appear to be a result of decreased cholesterol rather than increased lathosterol. A patient initially described as atypical SLOS with mucolipidosis was shown to have lathosterolosis by biochemical and molecular analysis. We identified a homozygous mutation of SC5D (137A>C, Y46S) in this patient. An unique aspect of the lathosterolosis phenotype is the combination of a malformation syndrome with an intracellular storage defect.

Lathosterolosis: A Disorder of Cholesterol Biosynthesis Resembling Smith-Lemli-Opitz Syndrome

“…It might already be present before commencement of treatment. Liver diseases were also reported in the other two lathosterolosis patients (Brunetti-Pierri et al 2002;Rossi et al 2005Rossi et al , 2007Krakowiak et al 2003). Although there are some adult studies suggesting cataract as an adverse effect of statin (Hippisley-Cox and Coupland 2010), the causal relationship between cataract and statin use has not been fully established.…”

“…The bilateral small dot cataract with no visual significance could also be a manifestation of the disease. Except the stillborn, the other two lathosterolosis patients also had either unilateral or bilateral cataract (Rossi et al 2007;Krakowiak et al 2003). Furthermore, hereditary factor could not be completely ruled out as the patient's father also had bilateral small dot opacity without any visual significance.…”

“…It was first reported by Brunetti-Pierri in 2002(Brunetti-Pierri et al 2002. The second case was reported initially as apparent Smith-Lemli-Opitz syndrome by Parnes in 1990(Parnes et al 1990), but was subsequently diagnosed to have lathosterolosis by postmortem examination by Krakowiak et al in 2003(Krakowiak et al 2003. The third case was reported by Rossi in 2007 who followed up on the first case reported by Brunetti-Pierri and described her affected sibling who was a stillborn (Rossi et al 2007).…”

“…To our knowledge, our patient is the first lathosterolosis patient receiving a therapeutic trial of simvastatin. This drug was started at a low dose (0.2 mg/kg/day) and was Each sterol is given in percent of total sterols Table 3 Comparison of clinical features of reported lathosterolosis cases Case 1 (Fetus) (Rossi et al 2007) Case 2 (Brunetti-Pierri et al 2002) (Rossi et al 2007) Case 3 (Krakowiak et al 2003) (Parnes et al 1990) Case gradually stepped up to 1 mg/kg/day. The level of lathosterol successfully decreased from 81.6 mmol/L to 15.1 mmol/L within 4 weeks time (normal level: <18 umol/L) and remained at a relatively low level afterwards.…”

“…All four coding exons of SC5DL gene and their flanking intronic sequences were amplified from the genomic DNA by polymerase chain reaction (PCR) as previously described (Krakowiak et al 2003). The PCR product was purified using ExoSAP-IT (GE Healthcare) and direct sequencing was performed on both strands with the PCR primers and the Big Dye terminator 3.1 cycle sequencing kit (Applied Biosystems) using an ABI-3730XL genetic analyzer.…”