NOVEL MUTATION IN THE APOB GENE (Apo B-15.56):
A CASE REPORT
Bove M1, Carnevali L, Cicero AFG, Tarugi P, Gaddi AV
*Corresponding Author: Marilisa Bove, “GC. Descovich” Atherosclerosis and Metabolic Disease
Research Unit, Internal Medicine, Aging & Kidney Diseases Department, University of Bologna,
Policlinico S.Orsola, Malpighi, Via Massarenti 9, 40138 Bologna, Italy; Tel./FAX: +39-(0)516-363-262;
E-mail: marilisa.bove@aosp.bo.it
page: 65
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INTRODUCTION
Familial hypobetalipoproteinemia (FHBL) is
a genetic disorder of lipid metabolism, transmitted
as a co-dominant trait, whose frequency in the
heterozygous form (as estimated by clinical criteria)
is 1:500-1:1000 [1]. This condition is characterized
by plasma levels of total cholesterol (TC),
low density lipoprotein-cholesterol (LDL-c) and
apolipoprotein-B (Apo-B) below the 5th percentile
for the general population [2]. Most cases of FHBL
are linked to nonsense/frameshift mutations of the
APOB gene, located on chromosome 2, which prevent
the complete translation of Apo-B mRNA and
lead to the production of truncated forms of Apo-B
[3]. More than 60 such mutations have been reported,
and they are designated by reference to the size
of the truncated form compared to the normal form
Apo-B 100 [4].
Apo-B 100 is a β lipoprotein synthesized by the
liver, consists of 4,536 amino acids and is present in
very low density lipoprotein (VLDL), intermediate
density lipoprotein (IDL) and low density
lipoprotein (LDL) of plasma. Another product of
the APOB gene it is Apo-B 48, that consists of
2,152 amino acids and results from an edited form
of Apo-B mRNA. Apo-B 48 is synthesized in the
small intestine and is present in chylomicrons (5).
The truncated forms of Apo-B may be secreted
into the plasma along with plasma lipoproteins. Only truncated Apo-B with a size above that of
apoB-29/30 are secreted and can be detected by
immunoblot with specific antibodies. Shorter
truncations are less frequent, as they represent
approximately one-third of all mutations, and
cannot be detected in plasma [6,7]. Unfortunately,
FHBL tend to be more severe in carriers of shorter
truncations (2). In patients affected by FHBL, the
mutant forms of Apo-B have a lower capacity for
transporting triglycerides, while the production
rate of the normal Apo-B 100 is reduced (usually to
25% of normal) [8]. This leads to a dysfunctional
VLDL system that increases the susceptibility of
the liver to the accumulation of lipids [1,9]. Fatty
liver disease (FLD) and mild elevation of liver
enzymes in serum are the main clinical features
of FHBL, but oral fat intolerance and intestinal fat
malabsorption have also been reported [1,2]. The
increase of hepatic fat reported in FHBL subjects
is not due to generalized or localized obesity, but
rather to the Apo-B mutations per se [7]. In fact,
intra-hepatic triglyceride content is not associated
with IR in FHBL, suggesting that it represents a
marker, not the cause, of metabolic dysfunction
[10]. On the other hand, a significant decrease in
arterial stiffness is observed in patients affected
by FHBL compared with healthy controls, despite
similar carotid intima-media thickness (IMT) [11].
This finding is consistent with a reduced lifelong
exposure to Apo-B containing particles and
suggests that FHBL could play a protective role
towards cardiovascular disease (CVD). However,
there is no systematic data about the prevalence
of CVD in FHBL, and convincing evidences of a
protective effect of lifelong reduction of plasma
LDL-c level toward atherosclerosis have only been
emerging recently [12]. Here we report a novel
mutation of the Apo-B 100 gene (Apo B-15.56),
in a rural South Italian family, and describe the
phenotypic manifestations.
Case Presentation. O.P., a 48-year old man,
was referred to our outpatients’ clinic for a careful
evaluation of his serum lipid levels which were
apparently inconsistent with a diagnosis of MS.
He had no history of smoking and his past medical
history was significant only for hypertension, for
which he was on antihypertensive medications.
On physical examination the patient was obese
(Body Mass Index = 32 kg/m2; waist circumference
= 105 cm), and his blood pressure was 130/85
mm Hg. His liver was palpable 2 cm below the
right costal margin. The remainder of the physical
examination was unremarkable. A recent ultrasound
imaging of the abdomen showed a severe hepatic
steatosis (Figure 1). He had diffused atheromasic
IMT in the following vascular regions: carotid
arteries, abdominal aorta and iliac-femoral arteries,
as documented by B-mode ultrasonographic
examination. Maximum reported thickness was 1.3
mm bilaterally at the bifurcation of the common
carotid artery (Figure 2). Laboratory testing showed
plasma values of TC, LDL-c and Apo-B less than
the 5th percentile, fasting plasma glucose 102 mg/
dL and basal plasma insulin 24.2 microUI/mL.
Family study revealed that his two children (O.G.,
male, 25 years old; and O.R., female, 23 years old) had a similar lipid phenotype (Figure 3) but
moderate increase of insulin serum level (O.G.:
22.1 microUI/mL; O.R: 19.5 microUI/mL) and
waist circumference values (O.G. = 97 cm; O.R. =
83 cm).
A genetic study was then performed on the
proband and his family. Genomic DNA was
extracted from peripheral blood leukocytes by
a standard procedure [13]. A single nucleotide
deletion on exon 15 of the APOB gene was
identified by polymerase chain reaction (PCR)
amplification with adapted primers [14]. The
amplification product was analyzed by 2%
agarose gel electrophoresis and sequenced using
Thermosequenase radiolabeled terminator cycle
sequencing kit (Amersham Biosciences Europe
GmbH, Freiburg, Germany) [15]. The identified
mutation is predicted to form a truncated Apo-B
species which we have designated Apo B-15.56. In
this case we decided to treat O.P. with metphormin
and acetylisalicylic acid in order to improve IR
(marked by severe hepatic-steatosis), and to slow
the progression of the atheromasic lesions, most
likely due to metabolic disorders and obesity. We
prescribed to both children a program of aerobic
exercise and balanced diet for gradual weight loss
and reduction of waist circumference.
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