© 1999 Nature America Inc. • http://genetics.nature.

com letter

The gene encoding ATP-binding cassette transporter 1 is

mutated in Tangier disease
Marek Bodzioch1, Evelyn Orsó1, Jochen Klucken1, Thomas Langmann1, Alfred Böttcher1, Wendy Diederich1,
Wolfgang Drobnik1, Stefan Barlage1, Christa Büchler1, Mustafa Porsch-Özcürümez1, Wolfgang E. Kaminski1,
Harry W. Hahmann2, Kurt Oette3, Gregor Rothe1, Charalampos Aslanidis1, Karl J. Lackner1 & Gerd Schmitz1

Tangier disease (TD) is an autosomal recessive disorder of lipid
metabolism1. It is characterized by absence of plasma high-
density lipoprotein (HDL) and deposition of cholesteryl esters
in the reticulo-endothelial system with splenomegaly and
enlargement of tonsils and lymph nodes2. Although low HDL
cholesterol is associated with an increased risk for coronary
artery disease, this condition is not consistently found in TD
pedigrees. Metabolic studies in TD patients have revealed a
rapid catabolism of HDL and its precursors2. In contrast to nor-
© 1999 Nature America Inc. • http://genetics.nature.com
expected to impair the function of the gene product. The
identification of ABC1 as the TD locus has implications for the
understanding of cellular HDL metabolism and reverse choles-
terol transport, and its association with premature cardio-
vascular disease.
We have recently demonstrated by differential display that ABC1
is regulated by HDL-mediated lipid export in human
macrophages11. Members of the ABC transporter family are
involved in transmembrane transport of substances such as ions,

mal mononuclear phagocytes (MNP), MNP from TD individuals
degrade internalized HDL in unusual lysosomes, indicating a
defect in cellular lipid metabolism3,4. HDL-mediated choles-
terol efflux and intracellular lipid trafficking and turnover are
abnormal in TD fibroblasts5–7, which have a reduced in vitro
growth rate8. The TD locus has been mapped to chromosome
9q31 (ref. 9). Here we present evidence that TD is caused by
mutations in ABC1, encoding a member of the ATP-binding
cassette (ABC) transporter family, located on chromosome
9q22–31 (ref. 10). We have analysed five kindreds with TD and
identified seven different mutations, including three that are
amino acids, peptides, sugars, vitamins, steroid hormones, bile
acids and phospholipids12–15. Diseases including cystic fibrosis,
X-linked adrenoleukodystrophy and Stargardt macular dystro-
phy have been linked to defects in ABC transporter genes16–18.
Therefore, we considered ABC1 a functional as well as a posi-
tional candidate for TD and analysed the gene in five TD families
(ten TD patients; Fig. 1). Individuals from four pedigrees have
been previously reported3–5,19–21. All Tangier patients had low
plasma levels of HDL-cholesterol (HDL-C), apolipoprotein
(apo) A-I, apoA-II and increased levels of triglycerides (Table 1).
Most obligate heterozygous individuals had subnormal plasma

Fig. 1 Pedigrees of TD kindreds. Affected TD individuals are represented by filled symbols and
heterozygous family members by half-filled symbols. We analysed 36 individuals, including 10
affected TD patients, for mutations in ABC1. Individuals designated with question marks were
not available for analyses. Bars indicate mutations identified in the respective alleles.

1Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, D-93042 Regensburg, Germany. 2Klinik Schwabenland, Waldburgallee 5,
D-88315 Isny-Neutrauchburg, Germany. 3Medical Faculty of the University of Cologne, D-50924 Koeln, Germany. Correspondence should be addressed to
G.S. (e-mail: gerd.schmitz@klinik.uni-regensburg.de).

nature genetics • volume 22 • august 1999 347

 letter © 1999 Nature America Inc. • http://genetics.nature.com

Table 1 • Demographic and lipoprotein data

Kindred Sex Age C TG HDL-C LDL-C ApoA-I ApoA-II

TD1 I:2 F 93 192 84 39 136 126 24.3
II:1 M 68 162 84 30 115 106 19.8
II:3 F 66 142 376 1 108 <20 <4.6
II:5 M 63 90 304 2 27 <20 <4.6
II:6 F 45 242 164 85 124 249 49.2
II:7 M 64 207 226 57 105 167 35.1
II:8 F 60+ 153 411 1 84 <20 <4.6
III:2 F 23 154 54 41 102 122 30.3
III:3 F 21 211 135 33 151 110 30.3
III:4 F 38 165 71 50 101 150 33.9
TD2 II:1 M 58 155 272 29 72 115 32.2
II:2 F 51 234 141 50 156 142 26.6
II:4 M 52 43 386 1 14 <20 <4.6
II:5 F 36 172 100 49 103 120 27.6
II:6 M 49 70 481 2 22 <20 <4.6
III:1 F 27 174 155 41 102 135 30.1
III:3 F 25 220 159 80 108 206 34.2
III:5 F 23 184 272 78 52 238 34.7
III:6 F 20 171 130 36 109 94 26.2
III:7 M 14 132 144 26 77 88 22.8
III:8 M 14 146 128 29 91 82 26.3
© 1999 Nature America Inc. • http://genetics.nature.com

TD3 II:3 F 69 128 362 2 54 <20 <4.6

II:4 M 66 58 245 1 8 <20 <4.6
II:5 F 60 239 215 59 137 175 33.8
II:7 F 64 253 179 40 177 130 32.3
III:1 M 40 184 198 32 112 119 26.9
III:2 F 37 198 223 41 112 138 29.5
III:3 M 33 169 106 28 102 122 36.8
III:4 F 28 160 64 49 98 161 35.4
III:5 M 27 156 130 22 108 90 33.3
TD4 II:1 F 45 189 60 60 117 141 30.3
II:2 M 39+ 201 193 3 183 <20 <4.6
II:3 M 37 88 570 1 27 <20 <4.6
II:4 M 34 177 197 29 86 115 43.3
TD5 II:2 F 87 321 241 84 189 221 35.4
II:3 M 83 251 724 30 30 129 29.4
III:2 M 58 239 123 83 131 231 30.0
III:3 F 47 177 40 85 84 187 31.0
III:4 M 52 132 169 8 90 27 12.1
III:5 F 371 660 35 35 146 31.7
IV:1 M 30 219 227 52 122 155 33.2
IV:2 F 20 182 73 90 77 199 36.2
IV:3 M 31 222 215 49 130 149 37.8
IV:4 F 24 164 62 74 77 167 28.2
V:1 F 2 153 67 40 99 109 29.3
All lipid, lipoprotein, and apolipoprotein values are expressed in mg/dl. C, cholesterol; TG, triglycerides; LDL-C, low-density lipoprotein cholesterol.

HDL-C levels when gender differences were taken into account.
It should be noted that splenomegaly and hyperplasia of other
lymphoid tissues was a prominent symptom in all TD patients
from pedigrees TD2, TD3 and TD4, whereas premature coronary
artery disease was the major clinical manifestation in the patients
from pedigrees TD1 and TD5.
Genetic analysis of ABC1 sequence led us to the identification
of several structural alterations in this gene in patients with TD.
We detected a single-base deletion removing guanine at nt 1,764
(G1764del; Fig. 2) in pedigree TD1. This mutation, localized in
codon 548, creates a frameshift that leads to a premature transla-
tion stop 26 amino acids downstream of the deletion site. The
translation product is predicted to be non-functional because it
lacks 75% of the amino acid sequence, including all transmem-
brane regions and both ATP-binding cassettes (Fig. 3). All TD
patients in pedigree TD1 (II:3, II:5 and II:8) were homozygous
for this mutation (Fig. 1). In addition, family members identi-
fied as heterozygotes showed decreased HDL-C plasma levels
(Table 1).
The 2 TD patients from pedigree TD2 (Fig. 1, II:4 and II:6)
have a genomic deletion resulting in the loss of approximately
1,500 nt at the 3´ end of the ABC1 mRNA. Initially, we noticed
that RT-PCR with primers targeting the region extending across
exons 39–48 did not yield any products. To characterize the pre-
dicted deletion, we amplified intron 38 from control DNA
using primers located in the adjacent exons. The intron was
approximately 1 kb, and had been sequenced. We were able to
confine the location of the deletion break point to the first 150
nt of intron 38 using multiple primer pairs along intron 38. To
verify the mutation on the genomic level, we performed South-
ern-blot anlysis using two probes, each specific for ABC1 exons
flanking the deletion breakpoint. In both affected individuals
the upstream flanking probe (specific for exon 38, which imme-
diately precedes the deletion breakpoint) detected DNA frag-
ments that differ in size from those of normal controls (Fig. 4a).
As expected, a mixed pattern of bands was seen in the obligate
heterozygous child (TD2 III:8). The downstream probe (detect-
ing the last exon 48) did not hybridize to genomic DNA in TD
patients. We found less intense bands in the heterozygous child
than in normal controls (Fig. 4b). The deletion detected in
pedigree TD2 predicts the synthesis of a defective protein that
lacks the 427 carboxy-terminal amino acids, that is the last

348 nature genetics • volume 22 • august 1999

 © 1999 Nature America Inc. • http://genetics.nature.com
Fig. 2 Sequence analysis of the ABC1 region containing the G1764del
frameshift mutation in pedigree TD1. Sequence analysis in a healthy control
individual (a), an obligatory heterozygous individual (III:2, b) and patient II:5
(c) is shown. The deletion of nt 1,764, which leads to a premature termination
of translation 26 aa downstream of the mutation site, is indicated (arrow).
transmembrane region and the complete second intracellular
ATP-binding fold, an essential part of full-size ABC trans-
porters. It can be assumed that this mutation also leads to the
formation of a gene product with a compromised if not absent
function.
Both TD individuals in kindred TD3 (II:3 and II:4) were
homozygous for an A2744G substitution (Fig. 5a–c) that
changes asparagine to serine (N875S) in the highly conserved
Walker A motif of the amino-terminal ATP-binding fold
(Fig. 3). The consensus sequence for the Walker A motif present
in all known ABC transporters is GxxGxGKT/S. It has been
shown that exchanges of the glycine residues or the lysine can
compromise the biologic function of ABC transporters22,23. The
mutation detected in TD3 does not affect these amino acids, but
the identical exchange of asparagine 965 to serine in the first
© 1999 Nature America Inc. • http://genetics.nature.com
Walker A motif GHNGAGKT of ABCR is responsible for Star-
gardt macular dystrophy18. All unaffected family members that
are heterozygous for the A2744G substitution showed subnor-
mal HDL-C plasma levels (Table 1).
In pedigrees TD4 and TD5 the affected individuals are com-
pound heterozygous at the ABC1 locus. A missense mutation,
C2750T, was found on one allele of all TD patients in pedigrees
TD4 (II:2, II:3) and TD5 (III:4; Fig. 5d). This mutation changes
alanine to valine (A877V) and is localized in the Walker A motif
of the N-terminal ATP-binding cassette, two amino acids away
from the substitution found in kindred TD3. In analogy to the
mutations in TD3 and Stargardt disease, it can be hypothesized
that the exchange of the alanine flanking the central glycine in
the Walker A motif (GHNGAGKT) leads to loss of function. In
TD5 this mutation was found only in the affected TD patient
(III:4). He also has a second abnormal allele, G1709C (W530S).
In four generations, individuals from kindred TD5 who carried
the G1709C (W530S) allele were characterized by subnormal
HDL-C levels (Table 1). This mutation affects a highly conserved
region in the first intracellular domain. It corresponds to amino
acid 605 of the ABCR protein. In fact, two missense mutations
affecting amino acids 602 and 608 in ABCR have been reported
in Stargardt disease24, suggesting that this region has a critical
function that is disturbed by non-conservative amino acid
exchanges.
In pedigree TD4, the two TD patients and both unaffected
siblings (II:1, II:4) are heterozygous for the C2750T (A877V)
nature genetics • volume 22 • august 1999
letter
a
homozygous
wild-type
b
heterozygous
c
homozygous
mutant
mutation. One unaffected sibling (II:4) has subnormal HDL-
C. The second allele in the two affected patients has two mis-
sense mutations, T1136C (V339A) and A2589G (I823M). Due
to the limited number of family members that were available,
we did not establish which of these two missense mutations
affects the function of the gene product. It should be noted that
the A2589G substitution is localized in the putative phospho-
rylation site of cAMP/cGMP-dependent protein kinase,
approximately 50 amino acids upstream of the Walker A motif
in the N-terminal ATP-binding cassette. Sequence analysis of
ABC1 regions containing the mutations G1709C (W530S),
G1764del, A2744G (N875S) and C2750T (A877V) did not
reveal any abnormalities in 200 chromosomes from healthy
volunteers.
Although mutations in ABC1 cause TD, the molecular mech-
anism remains unknown. Recent analysis by our group of Abc1-
null mice revealed a severe HDL deficiency and further
abnormalities consistent with TD (unpublished data). There-
fore, the Abc1-null mouse will be a model to complement stud-
ies of the human disease. Previous investigations on the
function of Abc1 in mice revealed its role in the engulfment of
apoptotic cells by macrophages25 and in macrophage inter-
leukin-1β secretion26.
Our results showing the involvement of ABC1 in TD and pre-
Fig. 3 Predicted topology and muta-
tions of ABC1. The principal functional
domains of ABC1 are shown. The posi-
tions of the missense mutations, the
single base pair deletion and the 3´
genomic deletion are indicated (aster-
isk and arrow, respectively).
349
 letter © 1999 Nature America Inc. • http://genetics.nature.com

a b

Fig. 4 Southern-blot analysis in pedigree TD2. Southern analysis is shown for two patients (II:4, II:6) and one obligate heterozygous child (III:8) from family TD2,
and four normal control individuals (N, N1, N3 and N4). DNA was digested with BamHI, EcoRI and HindIII as indicated. The blot was incubated with an exon 38
cDNA probe for ABC1 (a) or with an exon 48 cDNA probe in the presumably deleted region (b). The different fragment patterns present in TD patients II:4 and II:6
and the heterozygous child (a), and the absence of hybridization signals in the homozygous patients II:4 and II:6 (b) compared with controls, demonstrate the
presence of a genomic deletion. The lack of detectable fragments with the exon 38 probe in the BamHI digests of all individuals tested is probably due to a small
(<1 kb) genomic BamHI fragment, which runs out of the agarose gel.
© 1999 Nature America Inc. • http://genetics.nature.com

vious data demonstrating that ABC1 is cholesterol responsive11
suggest that this ABC transporter is a critical modulator of lipid
flux and cholesterol and phospholipid efflux. This most likely
links ABC1 to the major clinical manifestations observed in the
pedigrees analysed, which are splenomegaly caused by lipid
storage in the reticulo-endothelial system and early atherogene-
sis. All three TD patients in pedigree TD1 developed severe pre-
mature coronary artery disease, whereas the two TD patients in
TD3 are not affected or have only mild disease. This suggests
that different mutations in ABC1 may lead to different manifes-
tations of the disease. The deletion G1764del in TD1 almost
certainly leads to a complete loss of function, whereas the mis-
sense mutation A2744G (N875S) in TD3 may have different
effects on the function of ABC1.
The mechanisms by which cells export cholesterol and phos-
pholipids are not yet fully understood27. The detection of the
scavenger receptor B1 (SR-B1) as an HDL receptor has shed
some light on the interaction of HDL with cells28, but it appears
that SR-B1 is mainly required for the delivery of lipids to liver
and steroidogenic tissues. Its role in cholesterol and phospho-
lipid efflux is less well defined29. The identification of ABC1 as a
key regulator of cellular lipid and HDL metabolism will have
implications for our understanding of the mechanisms of cellu-
lar cholesterol homeostasis. In particular, it may influence our
current concepts of the molecular processes that lead to choles-
terol deposition and the initiation of atheromatous lesions in the
vascular wall.
Methods
Patients and pedigrees. In this study, we analysed individuals from five
kindreds with TD. Pedigrees TD1, TD2, TD3 and TD4 have been
described3–5,19–21. We collected whole blood and, in selected cases, skin
fibroblasts from TD family members after obtaining written informed
consent. Individuals TD1 II:8 and TD4 II:2 are deceased. We extracted
genomic DNA from cultured fibroblasts established at a previous time
point. Individuals TD1 I:1, TD4 I:2 and TD4 II:4 were potential heterozy-
gotes as suggested by previous reports and laboratory parameters.

Isolation of RNA and DNA. We isolated total RNA and DNA from cul-
tured skin fibroblasts or whole blood (anti-coagulated with EDTA). For
a preparation of total RNA from fibroblasts or leukocytes, we used the
homozygous
wild-type

RNeasy kit or the QIAamp RNA blood mini kit (Qiagen). We extracted
genomic DNA using the QIAamp DNA mini kit (fibroblasts) and the
QIAamp DNA blood midi or maxi kits (whole blood; Qiagen).

b
heterozygous

Amplification of DNA, cDNA synthesis and sequencing of PCR products.

We performed first strand cDNA synthesis and PCR amplifications on
9600 thermal cyclers (Perkin Elmer) using a commercially available kit
(Reverse Transcription System, Promega). PCR amplification products
were purified using Centricon 100 spin columns (Millipore). Purified PCR
products (30–60 ng) were cycle sequenced using BigDye terminators (DNA
homozygous

c
mutant

sequencing kit, PE Applied Biosystems), purified on CentriSep spin

columns and analysed on an ABI Prism 310 capillary sequencer (PE
Applied Biosystems).

d
heterozygous

Fig. 5 Sequence analysis of the N-terminal ABC1 Walker A region in kin-

dreds TD3, TD4 and TD5. Sequence analysis in a healthy control (a), a het-
erozygous individual (TD3 II:7, b) and the affected patient (TD3 II:4, c)
showing the A2744G mutation. The C2750T mutation present in pedigrees
TD4 and TD5 is indicated in (d). Both missense mutations are indicated
(arrows).

350 nature genetics • volume 22 • august 1999

 © 1999 Nature America Inc. • http://genetics.nature.com
Southern-blot analysis. Genomic DNA (8 µg) was completely digest-
ed in separate incubations with BamHI, EcoRI and HindIII, separated
on 0.7% agarose gels and transferred onto positively charged nylon
membranes (Roche). We incubated blots with ABC1-specific probes
targeting exons 38 or 48, respectively, and detected bands by non-
radioactive labelling in a Lumi-Imager F1 (DIG Luminescent Detec-
tion Kit, Roche).
GenBank accession number. ABC1, AJ012376.
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Acknowledgements
We thank U. Stöckl for molecular biological assistance; R. Glätzl, S. Potra and
D. Hant for technical help; G. Chimini for helpful discussions and providing
Abc1-null mice; and D. Bowyer for critical reading of the manuscript. This
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Received 2 June; accepted 28 June 1999.
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