BACKGROUND: Holoprosencephaly (HPE) is the most common
structural malformation of the developing forebrain in
humans. The aetiology is heterogeneous and remains
unexplained in approximately 75\% of patients. OBJECTIVE:
To examine cholesterol biosynthesis in lymphoblastoid cell
lines of 228 patients with HPE, since perturbations of
cholesterol homeostasis are an important model system to
study HPE pathogenesis in animals. METHODS: An in vitro
loading test that clearly identifies abnormal increase of
C27 sterols in lymphoblast-derived cells was developed
using 2-(14)C acetate as substrate. RESULTS: 22 (9.6\%)
HPE cell lines had abnormal sterol pattern in the in vitro
loading test. In one previously reported patient,
Smith-Lemli-Opitz syndrome was diagnosed, whereas others
also had clearly reduced cholesterol biosynthesis of
uncertain cause. The mean (SD) cholesterol levels were 57\%
(15.3\%) 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 six 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.
Division of Inborn Metabolic Diseases, University Hospital
for Pediatric and Adolescent Medicine, Heidelberg, Germany.
dorothea.haas@med.uni-heidelberg.de
%0 Journal Article
%1 haas.morgenthaler.ea:abnormal
%A Haas, D.
%A Morgenthaler, J.
%A Lacbawan, F.
%A Long, B.
%A Runz, H.
%A Garbade, S. F.
%A Zschocke, J.
%A Kelley, R. I.
%A Okun, J. G.
%A Hoffmann, G. F.
%A Muenke, M.
%D 2007
%J J Med Genet
%K /&/ Acetates, Adult; Carbon Cells, Chemicals, Child, Cholesterol, Chromatography-Mass Cultured; Female; Gas Holoprosencephaly, Humans; Infant, Infant; Lymphocytes, Male; Newborn; Organic Preschool; Radioisotopes; Reference Solvents, Spectrometry; Standards; Sterols, biosynthesis; isolation metabolism; purification/metabolism sfg
%N 5
%P 298--305
%R 10.1136/jmg.2006.047258
%T Abnormal sterol metabolism in holoprosencephaly: studies
in cultured lymphoblasts.
%U http://dx.doi.org/10.1136/jmg.2006.047258
%V 44
%X BACKGROUND: Holoprosencephaly (HPE) is the most common
structural malformation of the developing forebrain in
humans. The aetiology is heterogeneous and remains
unexplained in approximately 75\% of patients. OBJECTIVE:
To examine cholesterol biosynthesis in lymphoblastoid cell
lines of 228 patients with HPE, since perturbations of
cholesterol homeostasis are an important model system to
study HPE pathogenesis in animals. METHODS: An in vitro
loading test that clearly identifies abnormal increase of
C27 sterols in lymphoblast-derived cells was developed
using 2-(14)C acetate as substrate. RESULTS: 22 (9.6\%)
HPE cell lines had abnormal sterol pattern in the in vitro
loading test. In one previously reported patient,
Smith-Lemli-Opitz syndrome was diagnosed, whereas others
also had clearly reduced cholesterol biosynthesis of
uncertain cause. The mean (SD) cholesterol levels were 57\%
(15.3\%) 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 six 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.
@article{haas.morgenthaler.ea:abnormal,
abstract = {BACKGROUND: Holoprosencephaly (HPE) is the most common
structural malformation of the developing forebrain in
humans. The aetiology is heterogeneous and remains
unexplained in approximately 75\% of patients. OBJECTIVE:
To examine cholesterol biosynthesis in lymphoblastoid cell
lines of 228 patients with HPE, since perturbations of
cholesterol homeostasis are an important model system to
study HPE pathogenesis in animals. METHODS: An in vitro
loading test that clearly identifies abnormal increase of
C27 sterols in lymphoblast-derived cells was developed
using [2-(14)C] acetate as substrate. RESULTS: 22 (9.6\%)
HPE cell lines had abnormal sterol pattern in the in vitro
loading test. In one previously reported patient,
Smith-Lemli-Opitz syndrome was diagnosed, whereas others
also had clearly reduced cholesterol biosynthesis of
uncertain cause. The mean (SD) cholesterol levels were 57\%
(15.3\%) 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 six 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.},
added-at = {2017-04-01T10:34:58.000+0200},
author = {Haas, D. and Morgenthaler, J. and Lacbawan, F. and Long, B. and Runz, H. and Garbade, S. F. and Zschocke, J. and Kelley, R. I. and Okun, J. G. and Hoffmann, G. F. and Muenke, M.},
biburl = {https://www.bibsonomy.org/bibtex/2ba2d5bc844cb0e63df8762af53d73889/sveng},
doi = {10.1136/jmg.2006.047258},
institution = {Division of Inborn Metabolic Diseases, University Hospital
for Pediatric and Adolescent Medicine, Heidelberg, Germany.
dorothea.haas@med.uni-heidelberg.de},
interhash = {342132e33fb82ce2113df8d10470ac6e},
intrahash = {ba2d5bc844cb0e63df8762af53d73889},
journal = {J Med Genet},
keywords = {/&/ Acetates, Adult; Carbon Cells, Chemicals, Child, Cholesterol, Chromatography-Mass Cultured; Female; Gas Holoprosencephaly, Humans; Infant, Infant; Lymphocytes, Male; Newborn; Organic Preschool; Radioisotopes; Reference Solvents, Spectrometry; Standards; Sterols, biosynthesis; isolation metabolism; purification/metabolism sfg},
month = May,
number = 5,
owner = {sfg},
pages = {298--305},
pii = {jmg.2006.047258},
pmid = {17237122},
timestamp = {2017-04-01T10:35:16.000+0200},
title = {Abnormal sterol metabolism in holoprosencephaly: studies
in cultured lymphoblasts.},
url = {http://dx.doi.org/10.1136/jmg.2006.047258},
volume = 44,
year = 2007
}