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

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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