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Abnormal sterol metabolism in holoprosencephaly: Studies in cultured lymphoblasts
  1. Dorothea Haas (dorothea.haas{at}med.uni-heidelberg.de)
  1. University Hospital for Pediatric and Adolescent Medicine, Heidelberg, Germany
    1. Janine Morgenthaler (janine.morgenthaler{at}med.uni-heidelberg.de)
    1. University Hospital for Pediatric and Adolescent Medicine, Heidelberg, Germany
      1. Felicitas Lacbawan (flacbawa{at}nhgri.nih.gov)
      1. National Institutes of Health, Bethesda, United States
        1. Bob Long (blong{at}mail.nih.gov)
        1. National Institutes of Health, Bethesda, United States
          1. Heiko Runz (runz{at}embl.de)
          1. Institute of Human Genetics, University Hospital Heidelberg, Germany
            1. Sven F Garbade (sven.garbade{at}med.uni-heidelberg.de)
            1. University Hospital for Pediatric and Adolescent Medicine, Heidelberg, Germany
              1. Johannes Zschocke (johannes.zschocke{at}med.uni-heidelberg.de)
              1. Institute of Human Genetics, University Hospital Heidelberg, Germany
                1. Richard I Kelley (rkelley3{at}jhmi.edu)
                1. The Kennedy Krieger Institute and Department of Pediatrics, Johns Hopkins University, Baltimore, United States
                  1. Juergen G Okun (juergen.okun{at}med.uni-heidelberg.de)
                  1. University Hospital for Pediatric and Adolescent Medicine, Heidelberg, Germany
                    1. Georg F Hoffmann (georg.hoffmann{at}med.uni-heidelberg.de)
                    1. University Hospital for Pediatric and Adolescent Medicine, Heidelberg, Germany
                      1. Maximilian Muenke (mamuenke{at}mail.nih.gov)
                      1. Medical Genetics Branch, National Institutes of Health, Bethesda, United States

                        Abstract

                        Objective: Holoprosencephaly (HPE) is the most common structural malformation of the developing forebrain in humans. The etiology is heterogeneous and remains unexplained in approximately 75% of patients. Because perturbations of cholesterol homeostasis are an important model system to study HPE pathogenesis in animals, we examined cholesterol biosynthesis in lymphoblastoid cell lines of 228 HPE patients.

                        Methods: Using [2-14C]acetate as substrate, we developed an in vitro loading test that clearly identifies abnormal elevations of C27 sterols in lymphoblast-derived cells.

                        Results: Twenty-two HPE cell lines (9.6%) had abnormal sterol pattern in the in vitro loading test. In one previously reported patient, Smith-Lemli-Opitz syndrome (SLOS) was diagnosed, whereas others also had clearly reduced cholesterol biosynthesis of uncertain cause. The mean (SD) cholesterol level was 58 (15.4)% and 82 (4.7)% of total sterols in these cell lines and controls, respectively. The pattern of accumulating sterols was different from known defects of cholesterol biosynthesis. In 6 of the patients with abnormal lymphoblast cholesterol metabolism, additional mutations in genes known to be associated with HPE or chromosomal abnormalities were observed.

                        Conclusions: Impaired cholesterol biosynthesis may be a contributing factor in the cause of HPE and should be considered in the evaluation of causes of HPE, even if mutations in HPE-associated genes have already been found.

                        • Smith-Lemli-Opitz syndrome
                        • cholesterol biosynthesis
                        • cholesterol precursors
                        • holoprosencephaly

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