Lathosterolosis, a novel multiple-malformation/mental retardation syndrome due to deficiency of 3beta-hydroxysteroid-delta5-desaturase

Abstract

We report the clinical, biochemical, and molecular characterization of a patient with a novel defect of cholesterol biosynthesis. This patient presented with a complex phenotype, including multiple congenital anomalies, mental retardation, and liver disease. In the patient's plasma and cells, we found increased levels of lathosterol. The biosynthesis of cholesterol in the patient's fibroblasts was defective, showing a block in the conversion of lathosterol into 7-dehydrocholesterol. The activity of 3beta-hydroxysteroid-Delta(5)-desaturase (SC5D), the enzyme involved in this reaction, was deficient in the patient's fibroblasts. Sequence analysis of the SC5D gene in the patient's DNA, showing the presence of two missense mutations (R29Q and G211D), confirmed that the patient is affected by a novel defect of cholesterol biosynthesis.

Figure 1

Cholesterol biosynthetic pathway—schematic representation of the main 27-carbon sterol intermediates derived from 30-carbon lanosterol. Enzymatic defects associated with the distal Kandutsch-Russell pathway have already been described in human and mouse. Desaturation of the C5 bond may occur at two different steps in the pathway: 7-dehydrocholesterol is generated from the action of C5 sterol desaturase on lathosterol (cholest-7-en-3β-ol); this enzyme also acts on zymostenol (cholest-8[9]-en-3β-ol), generating 8-dehydrocholesterol. The enzymatic steps shown are as follows: (1) 3β-hydroxysteroid-Δ⁷-reductase (7-dehydrocholesterol reductase; E.C. 1.3.1.21), defective in SLO syndrome; (2) 3β-hydroxysteroid-Δ⁸,Δ⁷-isomerase (zymostenol isomerase; E.C. 5.3.3.5) defective in CDPX2 and tattered mouse; (3) C3 sterol dehydrogenase (NSDHL) defective in bare patches mouse and CHILD syndrome; and (4) SC5D.

Figure 2

Lathosterolosis phenotype. A, Postaxial hexadactyly of the left foot, with syndactyly between the 2nd–4th toes and between the 5th toe and the extra digit. B, Proband at age 3 years. Facial dysmorphisms include microcephaly, micrognathia, bilateral epicanthus, broad nasal bridge with anteverted nares, long philtrum, thin lips with prominent upper lip, and ogival palate.

Figure 3

Sterol profiles in proband with lathosterolosis. Typical GC/MS analysis of plasma from the proband (top) and from an unaffected control individual (bottom). The compounds definitively identified are as follows: (1) internal standard (5α-cholestane); (2) cholesterol; (3) zymostenol (cholest-8[9]-en-3β-ol); (4) lathosterol (cholest-7-en-3β-ol). The compounds tentatively identified are as follows: (5) 4-methylcholest-8[9]-en-3β-ol; and (6) 4,4-dimethylcholest-8[9]-en-3β-ol.

Figure 4

Cholesterol biosynthesis in control, lathosterolosis, and SLO fibroblasts. The percentage of recovered radioactivity is reported (mean ± SD of three different experiments). In control fibroblasts, 84.0%±18% of the incorporated radioactivity was recovered in the cholesterol fraction; in SLO fibroblasts, 78.2%±1.6% of the radioactivity was present as 7-dehydrocholesterol, and 14.0%±1.8% of the radioactivity was present as lathosterol. In the proband, of the total radioactivity, cholesterol represented 30.0%±11.0%, 7-dehydrocholesterol represented 3.4%±2.9%, and lathosterol represented 66.1%±10%.