- J Clin Invest. 1995 Nov;96(5):2152-61.
apo B gene knockout in mice results in embryonic lethality in homozygotes and
neural tube defects, male infertility, and reduced HDL cholesterol ester and apo
A-I transport rates in heterozygotes.
Huang LS(1), Voyiaziakis E, Markenson DF, Sokol KA, Hayek T, Breslow JL.
(1)Laboratory of Biochemical Genetics and Metabolism, Rockefeller University, New
York 10021, USA.
apo B is a structural constituent of several classes of lipoprotein particles,
including chylomicrons, VLDL, and LDL. To better understand the role of apo B in
the body, we have used gene targeting in embryonic stem cells to create a null
apo B allele in the mouse. Homozygous apo B deficiency led to embryonic
lethality, with resorption of all embryos by gestational day 9. Heterozygotes
showed an increased tendency to intrauterine death with some fetuses having
incomplete neural tube closure and some live-born heterozygotes developing
hydrocephalus. The majority of male heterozygotes were sterile, although the
genitourinary system and sperm were grossly normal. Viable heterozygotes had
normal triglycerides, but total, LDL, and HDL cholesterol levels were decreased
by 37, 37, and 39%, respectively. Hepatic and intestinal apo B mRNA levels were
decreased in heterozygotes, presumably contributing to the decreased LDL levels
through decreased synthesis of apo B-containing lipoproteins. Kinetic studies
indicated that heterozygotes had decreased transport rates of HDL cholesterol
ester and apo A-I. As liver and intestinal apo A-I mRNA levels were unchanged,
the mechanism for decreased apo A-I transport must be posttranscriptional.
Heterozygotes also had normal cholesterol absorption and a normal response of the
plasma lipoprotein pattern to chronic consumption of a high fat, high
cholesterol, Western-type diet. In summary, we report a mouse model for apo B
deficiency with several phenotypic features that were unexpected based on
clinical studies of apo B-deficient humans, such as embryonic lethality in
homozygotes and neural tube closure defects, male infertility, and a major defect
in HDL production in heterozygotes. This model presents an opportunity to study
the mechanisms underlying these phenotypic changes.
PMID: 7593600 [Indexed for MEDLINE]
- Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10903-7.
A novel functional role for apolipoprotein B in male infertility in heterozygous
apolipoprotein B knockout mice.
Huang LS(1), Voyiaziakis E, Chen HL, Rubin EM, Gordon JW.
(1)Department of Medicine, Columbia University, College of Physicians and
Surgeons, New York, NY 10032, USA. email@example.com
Male infertility, affecting as many as 10% of the adult population, is an
extremely prevalent disorder. In most cases, the cause of the condition is
unknown, and genetic factors that might affect male fertility, other than some
sequences on the Y chromosome, have not been identified. We report here that male
mice heterozygous for a targeted mutation of the apolipoprotein B (apo B) gene
exhibit severely compromised fertility. Sperm from these mice failed to fertilize
eggs both in vivo and in vitro. However, these sperm were able to fertilize eggs
once the zona pellucida was removed but displayed persistent abnormal binding to
the egg after fertilization. In vitro fertilization-related and other experiments
revealed reduced sperm motility, survival time, and sperm count also contributed
to the infertility phenotype. Recognition of the infertility phenotype led to the
identification of apo B mRNA in the testes and epididymides of normal mice, and
these transcripts were substantially reduced in the affected animals. Moreover,
when the genomic sequence encoding human apo B was introduced into these animals,
normal fertility was restored. These findings suggest that this genetic locus may
have an important impact on male fertility and identify a previously unrecognized
function for apo B.
PMID: 8855280 [Indexed for MEDLINE]