A Truncated Species of Apolipoprotein B (B-38.7) in a
Patient With Homozygous Hypobetalipoproteinemia
Associated With Diabetes Mellitus
Ken Ohashi, Shun Ishibashi, Michiyo Yamamoto, Jun-ichi Osuga, Yoshio Yazaki,
Susumu Yukawa, Nobuhiro Yamada
Abstract—Familial hypobetalipoproteinemia is caused by mutations in the apolipoprotein (apo) B gene. We identified a57-year-old woman whose plasma total cholesterol and apoB levels were 2.17 mmol/L and 0.03 g/L, respectively.
Separation of plasma lipoproteins by sodium dodecyl sulfate–polyacrylamide gel electrophoresis revealed the absenceof apoB-100 and the presence of a faster-migrating form of apoB with an apparent Mr of 195 kDa. Direct sequencing
of a polymerase chain reaction–amplified fragment of the patient’s apoB gene DNA revealed a single C3 T transitionat nucleotide 5472 that converts glutamine 1755 (CAA) to a stop codon (TAA). We predict this novel nonsense mutationof the apoB gene to produce a truncated protein that contains 1754 amino-terminal amino acid residues of apoB-100.
We designated this mutant form of apoB apoB-38.7 by following the centile nomenclature of the apoB species. The
same mutation was found in both of her children. The proband revealed clinical findings of retinitis pigmentosa,
acanthocytosis, and loss of deep tendon reflexes that are characteristic of severe hypobetalipoproteinemia. In addition,
the proband had type II diabetes mellitus with nephropathy, anemia, cholelithiasis, hepatic hemangioma, bronchiectasis,and extensive calcification of major arteries including, the celiac, splenic, and renal. In summary, we have found a novel
truncated apoB, apoB-38.7, in a patient with an unusual presentation of hypobetalipoproteinemia that includes diabetes
mellitus and extensive arterial calcification. (Arterioscler Thromb Vasc Biol. 1998;18:1330-1334.)
Key Words: diabetes mellitus n retinitis pigmentosa n proteinuria n arterial calcification n peripheral neuropathy
amilial hypobetalipoproteinemia (HBLP)1 is a codominant genetic disorder characterized by decreased or absent plasma levels of apolipoprotein (apo) B. (See References
1 and 2 for a review.) Heterozygotes for HBLP have plasma
levels of apoB below the fifth percentile and typically are
asymptomatic. In Western populations, the frequency of
HBLP heterozygotes is estimated between 1 in 500 and 1 in1000 persons.2 Homozygotes and compound heterozygotes
have extremely low levels of apoB. The clinical phenotype of
HBLP homozygotes is highly variable, with severe cases
presenting with fat malabsorption, acanthocytosis, retinitis
pigmentosa, and neurological complications resulting fromintestinal malabsorption of vitamin E. Symptoms observed insome patients with homozygous HBLP are indistinguishable
from those of patients with abetalipoproteinemia, a recessive
disease arising from mutations in microsomal triglyceridetransfer protein (MTP).3,4
Since Young and his colleagues5,6 demonstrated that mutations in the apoB gene cause HBLP, '30 mutations havebeen reported. Most of these mutations are nonsense orframeshift mutations that prevent the translation of the
full-length apoB-100 protein. In this report, we describe a

F

Japanese patient with homozygous HBLP caused by a novel
mutation in the apoB gene that gives rise to a truncated apoB
peptide, apoB-38.7.

Methods
Clinical Data
The proband (K.H.) is a 57-year-old Japanese woman who wasreferred to Wakayama Medical College for evaluation of a livermass. Past medical history was significant for childhood asthma,
night blindness, and type II diabetes mellitus diagnosed at age 36
years and managed by diet and insulin. At age 48 she had a retinal
hemorrhage due to hemorrhagic glaucoma, resulting in right eyeblindness despite photocoagulation therapy, and at age 54 shedeveloped hemoptysis secondary to bronchiectasis. There was no
history of diarrhea or steatorrhea. Family history was unremarkable,
although there was no reliable information on consanguinity. She
had 2 children, a 32-year-old (A.Y.) and a 30-year-old (H.H.) male,
who were the only family members accessible to us for medical
investigation.
Physical examination revealed a lean, pale woman 145 cm tall andweighing 37.5 kg. Pulse was 96 bpm and regular; blood pressure was
142/62 mm Hg. Visual acuity was lost in the right eye and 0.06/1.0
in the left with a narrow visual field. Intraocular pressure was
40 mm Hg in the right eye and 15 mm Hg in the left. Retinal
pigmentation, hard exudates, and extensive photocoagulation scars

Received September 17, 1997; revision accepted March 17, 1998.
From the Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo (K.O., S.I., J.i.-O., Y.Y., N.Y.), and the Third
Department of Internal Medicine, Wakayama Medical College, Wakayama (M.Y., S.Y.), Japan.
Correspondence to Shun Ishibashi, MD, Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7–3-1 Hongo, Bunkyo-ku,
Tokyo 113, Japan. E-mail ishibash-tky@umin.u-tokyo.ac.jp© 1998 American Heart Association, Inc.

1330

Ohashi et al

August 1998

1331

TABLE 1. Plasma Concentrations of Lipids, Apolipoproteins,and Vitamin E in the Kindred of K.H.
K.H.

A.Y.

H.H.

TC, mmol/L

2.17

3.21

3.28

TG, mmol/L

0.64

0.49

0.70

HDL-C, mmol/L

1.99

1.76

1.84

apoA-I, g/L

1.33

1.66

1.75

apoA-II, mg/L

200

370

420

apoB, mg/L

30

274

268

apoC-II, mg/L

32

16

21

apoC-III, mg/L

75

62

67

apoE, mg/L

35

34

36

Lp(a), mg/L

56

129

134

Vitamin E, mg/L

7

7

8

Lp(a) indicates lipoprotein(a). Apolipoprotein concentrations were measured
by the single radial immunodiffusion method.7 Lp(a) concentrations were
determined by ELISA. Vitamin E concentrations were determined by high-performance liquid chromatography.

were noted in both optic fundi. Gross hearing loss was noted in theright ear. Examination of the chest and abdomen was unremarkable.
Neurological examination revealed paresthesia in both hands,“stocking-glove” type hypesthesia, absent deep tendon reflexes in
the lower extremities, and positive Romberg’s sign. Examination
revealed no abnormal pyramidal, cerebellar, or posterior column
abnormalities. Laboratory tests revealed anemia (hemoglobin, 7g/dL) with acanthocytosis, proteinuria (0.6 to 2.3 g/d), mild hyperglycemia (fasting plasma glucose, 120 to 160 mg/dL; stable HbA1c,6.9%), and reduced creatinine clearance (40 mL/min). Plasma lipid
analysis showed that she was moderately hypocholesterolemic, withtotal cholesterol (TC) levels of 2.17 mmol/L, plasma triglycerides(TGs) of 0.64 mmol/L, HDL cholesterol of 1.99 mmol/L, and plasma
apoB of 0.03 g/L.7 Prothrombin time was 10.7 seconds. Plasma
concentrations of vitamins K1 and K2 were normal: 0.27 and ,0.05
ng/mL, respectively. Plasma cholesteryl ester transfer activity was
3.98 nmol z mL21 z min21 (normal value, 2.3960.32).8 A.Y. and H.H
were also hypocholesterolemic (3.2 to 3.3 mmol/L). The results oflipid analysis of K.H., A.Y., and H.H. are summarized in Table 1.
The electroretinogram was flat in both eyes. Abdominal CT scanrevealed extensive calcification of the major arteries, including
celiac, splenic, common hepatic, renal, and superior mesenteric anda segment of the abdominal aorta (Figure 1). Hepatic hemangioma
and cholelithiasis were found on ultrasonography and MRI. Liverbiopsy revealed mild fatty changes. After a 12-hour fast, theFigure 2. Microscopic examination of biopsied specimen fromduodenal mucosa. A, Hematoxylin-eosin staining of microvilli.
Enterocytes are apparently normal and do not contain vacuoles,
a hallmark of lipid accumulation. B, Electron microscopy of theluminal side of duodenal enterocytes. Electron-lucent lipid droplets are seen in the apical cytoplasm in some sections (magnification 310 000).

duodenal mucosa was biopsied endoscopically. Hematoxylin-eosin
staining of the biopsied specimen showed no evidence of lipid
accumulation in the enterocytes (Figure 2A). Transmission electron
microscopy revealed moderate accumulation of fat droplets in theapical cytoplasm of the enterocytes in some sections (Figure 2B).

Plasma Lipoprotein and Apolipoprotein Analyses
Blood samples were collected in EDTA-containing tubes. After
separation of blood cells for isolation of genomic DNA, the plasma
was mixed immediately with a protease inhibitor cocktail containing
EDTA, benzamidine, NaN3, and PMSF. For determination of thelipid contents in each lipoprotein fraction, VLDL (d,1.006 g/mL),
IDL (d51.006 to 1.019 g/mL), LDL (d51.019 to 1.063 g/mL),HDL2 (d51.063 to 1.125 g/mL), and HDL3 (d51.125 to 1.21 g/mL)
were isolated by sequential ultracentrifugation as previously described.9 TC, free cholesterol, and TGs were measured enzymatically. For the apolipoprotein analyses, VLDL1IDL (d,1.019g/mL), LDL, and HDL (d51.063 to 1.21 g/mL) were isolated.
After dialysis against a saline solution containing 10 mmol/L
phosphate buffer, pH 7.4, 0.15 mol/L NaCl, 1 mmol/L EDTA, and1 mmol/L PMSF, each lipoprotein fraction was delipidated andsubjected to SDS–polyacrylamide gel electrophoresis (PAGE, 3% to15%). Proteins were visualized by staining with Coomassie brilliant
blue R-250.

Haplotype Analyses and DNA Sequences of ApoB
Genomic DNA was prepared from blood cells with the use of a QIAampblood kit (Qiagen). The DNA fragments of a variable number of tandemly
repeated short DNA sequences (VNTR) in the 39 end of the apoB gene andCA repeats in intron 10 of the MTP gene were prepared as described.10,11 A
581-nucleotide (nt) DNA (nts 5271 to 5852) of the apoB gene was preparedby polymerase chain reaction (PCR) with the following primers: primer A(sense nts 5271 to 5294), 59-CAGGCCATGATTCTGGGTGTCGAC-39
and primer B (antisense nts 5873 to 5852), 59-CCCATTGCCATTTGTATGTGCATC-39 according to Collins et al.12 The amplified DNAs weredirectly sequenced by the dideoxy chain-termination method with the use of
an ABI 373 DNA sequencer (Perkin-Elmer Cetus, Applied Biosystems).

Other Mutations
The common cholesteryl ester transfer protein (CETP) gene mutations, an intron 14 splicing defect and an exon 15 missense mutation,
Asp442Gly, were evaluated as described.13,14
Figure 1. Abdominal CT scan. Four cross sections are shown(A to D, rostral to caudal). Hepatic hemangioma in the right lobe(A) and calcification of splenic (A and B), celiac (B), common
hepatic (B), renal (C), and superior mesenteric (D) arteries and asegment of abdominal aorta (D) are noted.

Results
Lipid contents in each lipoprotein fraction from K.H. areshown in Table 2. Note that LDL contained only
0.12 mmol/L TC. VLDL contained more TC than did LDL.

1332

ApoB-38.7, Hypobetalipoproteinemia, and Diabetes Mellitus

TABLE 2. Lipid Contents of Plasma Lipoproteins From K.H.
VLDL

IDL

LDL

HDL2

HDL3

TC, mmol/L

0.30

0.02

0.12

1.48

0.44

FC, mmol/L

0.12

0.01

0.05

0.54

0.08

TG, mmol/L

0.41

0.01

0.01

0.1

0.04

FC indicates free cholesterol. VLDL, IDL, LDL, HDL2, and HDL3 were isolated
by sequential ultracentrifugation.

Most of the TC, 81%, was present in HDL. The HDL2-C/
HDL3-C ratio was increased to 3.3.
We sought to identify the cause of K.H.’s hypocholesterolemia. We genotyped the 39 VNTR of the patient’s apoB
gene and the CA repeats in intron 10 of the MTP locus. The
patient was homozygous for the apoB locus (b37/b37) andheterozygous for the MTP locus. This finding is consistent
with the level of plasma TC found in homozygous HBLP and
the presence of immunoreactive apoB in plasma (Table 1).
Lipoproteins subjected to SDS-PAGE and Coomassie
staining revealed a protein of apparent Mr of 195 kDa in
VLDL, LDL, and HDL fractions but not in the d.1.21 g/mL
fraction (Figure 3). Neither apoB-100 nor apoB-48 was
detectable. Based on the apparent molecular weight of the
apoB moiety, we estimated a protein size of 1700 to 1800
amino acids. We prepared DNAs by PCR of the apoB geneflanking the site of the predicted mutation. Sequencing of the
prepared DNAs revealed a single C3 T transition at position
5472 that converts glutamine 1755 (CAA) to a stop codon(TAA) (Figure 4). The calculated centile fraction of themutant apoB is 38.7%, ie, 1754 of 4536 amino acids. We
designated this truncated apoB species apoB38.7, by following the centile nomenclature of the apoB species classification.15 We confirmed that both of the proband’s sons were
heterozygous for the identical mutation.

Figure 4. DNA sequences of apoB in the kindred of K.H.
Genomic DNA was prepared from blood cells. A 581-nt DNA(nts 5271 to 5852) of the apoB gene was prepared by PCR. The
amplified DNAs were directly sequenced by the dideoxy chaintermination method with an ABI 373 DNA sequencer (PerkinElmer Cetus, Applied Biosystems). K.H. had a single C3 T transition at position 5472 that converts glutamine 1755 (CAA) to astop codon (TAA). Both of the proband’s sons (A.Y. and H.H.)
were heterozygous for the identical mutation.

We suspected that the proband had a CETP deficiency
based on the elevated plasma HDL-C level (1.99 mmol/L)and the increased HDL2-C/HDL3-C ratio (3.3).16 We genotyped K.H.’s CETP gene for the common CETP genemutations, an intron 14 splicing defect and an exon 15
missense mutation, Asp442Gly, but neither mutation was
detected, supporting the finding of normal plasma CETP
activity in K.H.
Figure 3. SDS-PAGE analyses of plasma lipoproteins from K.H.
and a normal control subject. VLDL1IDL (V), LDL (L), and HDL(H) were isolated by sequential ultracentrifugation at densities of
1.019, 1.063, and 1.21 g/mL, respectively. After dialysis anddelipidation, 20 mg protein of each lipoprotein fraction (lanes 1
through 6) and 50 mg protein of HDL and the lipoproteindepleted fraction (d.1.21) (lanes 7 through 9) were subjected toSDS–3% to 15% PAGE. Proteins were visualized by staining
with Coomassie brilliant blue R-250. ApoB38.7 was visible inlanes 4, 5, and 7 but not in lane 9, indicating that this truncatedapoB is distributed from VLDL through HDL but not in thed.1.21 g/mL fraction.

Discussion
The results demonstrate a novel truncation mutation of apoB,
apoB-38.7, in the plasma from a patient with homozygous
HBLP. ApoB-38.7 is the result of a nonsense mutation at
Gln1755 that yields a protein 38.7% the size of apoB-100.
Homozygosity for the apoB38.7 allele is supported by homozygosity of the 39 VNTR allele of apoB. Both of theproband’s sons were found to be heterozygous for the mutant
allele.

Ohashi et al
Approximately 30 different mutations have been reported
to cause HBLP (see Reference 1 for a review and References
17 through 19), and only 6 were found to be present in thehomozygous state.12,18 –22 Patients with the most severe phenotype were siblings who were compound heterozygotes for
apoB-2 and apoB-9.23 The siblings’ LDL-C levels wereundetectable, and they presented with steatorrhea, neurological deficits, and retinitis pigmentosa, a complex of symptoms
clinically indistinguishable from that of abetalipoproteinemia.
An 8-year-old patient homozygous for apoB-50 also exhibited neurological abnormalities resulting from a nearly complete absence of vitamin E in the plasma.21 Neither neurological symptoms nor retinal degeneration was reported inpatients homozygous for apoB-25,20 apoB-27.6,18 apoB-29,12
apoB-39,12 and apoB-45.219 or compound heterozygous for
apoB-40/apoB-89.24 In particular, a 48-year-old patient homozygous for apoB-45.2 had a normal plasma level ofvitamin E.19 In this context, it is noteworthy that K.H. ishomozygous for apoB-38.7 and has neurological deficits,
retinal pigmentation, and a flat electroretinogram, the latter 2of which are indicative of retinitis pigmentosa, despite anormal plasma level of vitamin E (Table 1). Other confounding factors, such as long-standing diabetes mellitus andadvancing age, may account for the relatively severe clinicalpresentation of HBLP in K.H.
In addition to this complex of classic symptoms typical ofsevere HBLP, K.H. had a wide variety of conditions, such astype II diabetes mellitus, hepatic hemangioma, cholelithiasis,
proteinuria, and a history of retinal hemorrhage, hemoptysis,
and arterial calcification. Except for cholelithiasis, which has
been reported to be prevalent in the affected members of an
apoB-83 kindred,25 the significance of the constellation ofthese diseases within this patient is currently unknown. Theseflorid complications may be attributable to other recessive
mutations. Because HBLP is thought to be protective against
atherosclerosis, it is important to note that K.H. had severe
calcification of major arteries. One report indicates a relative
paucity of coronary artery morbidity and mortality among
first-degree relatives of patients with heterozygous HBLP26;
furthermore, the virtual absence of atherosclerosis was reported in a 76-year-old subject with HBLP.27
According to her medical history, K.H. had received
photocoagulation therapy for “hemorrhagic glaucoma,”
which presumably resulted from proliferative diabetic retinopathy. Her renal disease and peripheral neuropathy are also
compatible with the clinical picture of diabetic microangiopathy. Because hyperlipidemia is a risk factor for diabetic
retinopathy28 and cholesterol-lowering therapy retards the
progression of diabetic nephropathy,29 it is noteworthy that
she had advanced complications due to long-standing
diabetes.
Another remarkable finding is the unusually high plasma
TC and HDL-C levels of K.H. when compared with other
HBLP homozygotes. The high HDL2-C/HDL3-C ratio (Table
2)16 and the association with atherosclerosis30 in K.H. areconsistent with the clinical features of CETP deficiency,
which is a common cause of hyperhighdensitylipoproteinemia in the Japanese.13 However, CETP activity was notdecreased, and mutations in either intron 14 or exon 15 of theAugust 1998

1333

CETP gene, the most common mutations causing CETP
deficiency in the Japanese,13 were not found in the patient.
Therefore, it is unlikely that K.H. had CETP deficiency. The
associated proteinuria may, at least in part, account for the
exceptionally high TC levels in K.H.
We detected apoB-38.7 from VLDL through HDL but notin the d,1.21 g/mL fraction (Figure 3). Previous studies haveshown that the buoyant density of the apoB-containing
lipoproteins is largely proportional to the size of apoB
between apoB-31 and apoB-37. It has been reported that
apoB-31,31 apoB-32,32 and apoB-32.533 are present in thed.1.21 g/mL fraction, but apoB-37 is not,5 suggesting that a
portion of the apoB proteins between apoB-32.5 and apoB-37
is critical for the distribution to the d.1.21 g/mL fraction.
This finding is in agreement with our observation that
apoB-38.7 was not present in the d.1.21 g/mL fraction.
ApoB-37,5 apoB-38.9,17 apoB-40,34 and apoB-4635 were reported to be present in HDL, but apoB-39,12 apoB-50,21 andthe other species larger than apoB-50 were not, indicating thata portion of the apoB between apoB-37 and apoB-46 isessential for distribution in HDL. This finding is consistent
with our observation that apoB-38.7 was distributed in HDL.
In summary, we have found a novel, truncated apoB,
apoB-38.7, in a patient with an unusual presentation of
HBLP, including diabetes mellitus and extensive arterial
calcification.

Acknowledgments
We thank Dr R. Takatsuki for the ophthalmological evaluation of
K.H., S. Fukuda for electron microscopy, Drs S.G. Young and M.
Kinoshita for helpful comments, and Dr P.K. Frykman for criticalreading of the manuscript.

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