Functional data in the mouse and other model organisms
As nearly all human ABC genes have a one-to-one ortholog in the mouse
genome, murine knockouts and other modified alleles represent an
excellent source of functional information in animal models for ABC gene
diseases. Mutant alleles have been generated for all murine ABC genes
allowing for phenotypic screens. Specific phenotypes are reported for 46
of the 53 murine ABC genes (Table 2 ). The reported phenotypes
for mouse ABC genes are highly diverse. They include abnormal lipid,
cholesterol, and glucose levels, development of specific organ systems
such as the eye, adrenal gland, lung, liver, thyroid, male reproductive
tract, heart, spleen, thymus, arteries, lymphocytes, and brain. In mice,
disruption (homozygous knockout) of the Abca3 , Abcb7 ,Abcb10 , Abce1 , and Abcf1 genes results in embryonic
lethality, and Cftr /Abcc7 , Abcc9 , and thetrac allele in Abcg5 are associated with premature
lethality (Chase et al., 2010).
Many mouse ABC gene alleles recapitulate features of human Mendelian
disorders or known human ABC gene function. ABCA1 mutations in
humans cause Tangier disease characterized by the defective formation of
HDL particles, and Abca1 -/- mice also have HDL
deficiency. ABCA3 transports lipids into the lung’s lamellar bodies, and
mutations cause severe neonatal lung surfactant deficiency;Abca3 -/- mice have abnormal lung development
and morphology. ABCA4 flips retinoid-lipid complexes in photoreceptor
disks (Molday, Zhong, & Quazi, 2009). ABCA4 mutations cause
Stargardt disease and related maculopathies, characterized by excessive
lipofuscin (A2E) accumulation (Allikmets et al., 1997).Abca4 -/- mice also accumulate lipofuscin/A2E,
have abnormal dark adaptation, and thinning of the outer nuclear layer
(Mata et al., 2001). ABCA12 is expressed in the lamellar granules
of the skin, and mutations cause two forms of recessive congenital
ichthyosis (Kelsell et al., 2005; Lefevre et al., 2003).Abca12 -/- mice also have abnormal scaly skin.
Interestingly, Abca12 -/- mice also have lung
surfactant deficiency, lamellar body abnormalities, and alveolar
collapse, demonstrating an essential function in lipid transport in the
mouse lung.
ABCB1 encodes P-glycoprotein, an efflux transporter found
overexpressed in many chemotherapy multidrug-resistant tumor cell lines
and plays a vital role in eliminating xenobiotics.ABCB1 -/- collie dogs have sensitivity to
ivermectin toxicity (Mealey, Bentjen, Gay, & Cantor, 2001), andAbcb1a /Abcb1b -/- mice have an abnormal
distribution of compounds in the brain (Mason, Pariante, & Thomas,
2008). The TAP1 and TAP2 proteins (ABCB2 and ABCB3) together form a
transporter for peptides subsequently loaded onto class I HLA molecules,
and mutations in either gene cause immunodeficiency in humans, abnormal
T cell levels, and antigen presentation in the mouse (de la Salle et
al., 1994; Van Kaer, Ashton-Rickardt, Ploegh, & Tonegawa, 1992). ABCB4
transports phospholipids in bile and protein defects lead to recessive
intrahepatic cholestasis in both humans and mice.Abcb4 -/- mice also have extensive bone
developmental abnormalities (Dixon et al., 2000; Hochrath et al., 2013).
ABCC2 transports organic anions, including bile salts, and recessive
mutations cause Dubin-Johnson syndrome, a hereditary hyperbilirubinemia
(Wada et al., 1998). A rat model, the TR rat, andAbcc2 -/- mice have abnormal liver weight and
physiology, bile secretion, and composition (Vlaming et al., 2006).ABCC6 mutations cause pseudoxanthoma elasticum, a calcification
disorder, and ABCC6 facilitates the release of nucleoside triphosphates,
the source of pyrophosphate, and inhibitor of calcification (Bergen et
al., 2000; Jansen et al., 2013; Le Saux et al., 2000; K. Moitra et al.,
2017). Mouse Abcc6 -/- mice have abnormal skin
calcification and morphology (Gorgels et al., 2005). CFTR/ABCC7 encodes
a chloride ion channel that plays a crucial role in exocrine secretion
in the lung, intestine, pancreas, vas deferens, and skin, and recessive
mutations cause cystic fibrosis (Anguiano et al., 1992; Quinton, 1999).
Multiple Cftr mutations on different mouse backgrounds
recapitulate nearly all the features of the human disease (O’Neal et
al., 1993; Zeiher et al., 1995). ABCC8 and ABCC9 encode the sulfonylurea
receptors SUR and SUR2, and mutations in ABCC8 (Chutkow et al., 2001) in
humans cause non-insulin-dependent diabetes (Thomas et al., 1995).
Knockouts of either Abcc8 or Abcc9 cause hypoglycemia and
insulin abnormalities, and Abcc9 -/- mice also
die prematurely (Chutkow et al., 2001; Seghers, Nakazaki, DeMayo,
Aguilar-Bryan, & Bryan, 2000).
ABCD1 mutations in humans cause the X-linked
adrenoleukodystrophy; Abcd1 -/- mice display
abnormal myelination, brain cell morphology, astrocytosis, axon
degeneration, and impaired coordination. Interestingly,Abcd2 -/- mice manifest neuronal and axon
degeneration, ataxia, hyperactivity, tremors, abnormal microglial cell
morphology, posture, and coordination, suggesting that this protein also
functions in the brain (Ferrer et al., 2005). A family with a bile acid
synthesis defect and peroxisomal abnormalities displayed mutations in
ABCD3(?). In addition, Abcd3 -/- mice display
increased liver size, abnormal peroxisomes, and a deficit in mature C24
bile acids (Ferdinandusse et al., 2015). ABCG2 is a uric acid
transporter, and common variants in the ABCG2 gene are associated
with gout, a disorder of blood uric acid levels (Dehghan et al., 2008).Abcg2 -/- mice display sensitivity to
phytotoxins and increased blood and urine uric acid (Ichida et al.,
2012; Jonker et al., 2002). The ABCG5 and ABCG8 genes
encode half-transporters that function as a heterodimer and transport
phytosterols. Mutations in these genes cause recessive sitosterolemia in
humans and abnormal blood lipid and cholesterol levels in the mouse
(Chase et al., 2010; Klett et al., 2004).
Many mouse ABC gene mutations are associated with phenotypes likely to
be caused by a defect in cellular transport or provide clues to human
gene function. For example, the human ABCA2 gene is highly
expressed in the brain and closely related to the known lipid
transporters ABCA1, ABCA3, and ABCA4. Disruption of the mouseAbca2 gene leads to multiple behavioral and neurological
phenotypes and decreased body weight (Sakai et al., 2007). ABCA7 is also
a lipid transporter, and mouse Abca7 disruption mice exhibit
reduced HDL cholesterol, adipose tissue, and kidney size (Kim et al.,
2005). There is an ABCA5 -related gene cluster in all mammals, but
the function of these genes is unknown.Abca5 -/- mice display abnormal liver morphology
and physiology and develop an adult lethal dilated cardiomyopathy-like
heart phenotype. The protein locates primarily in the lysosomes (Kubo et
al., 2005). Abca6 knockout mice display decreased circulating
serum albumin, decreased total protein, and increased hematocrit.Abca8b -/- mice show diminished cholesterol, HDL
cholesterol, LDL cholesterol, and triglyceride levels, and humans withABCA8 mutations and low HDL cholesterol have been described
(Trigueros-Motos et al., 2017). Expression of the Abca9 gene is
principally in the brain (Piehler, Kaminski, Wenzel, Langmann, &
Schmitz, 2002).
The human ABCG1 and ABCG4 genes are evolutionarily related
to each other and the sterol transporters ABCG5 and ABCG8, but their
function in humans is unknown. The mouse Abcg1 knockout results
in the accumulation of neutral lipids and phospholipids in hepatocytes
and macrophages and plays a role in loading cholesterol onto HDL
particles (Kennedy et al., 2005). Loss of Abcg1 can affect the
immune function of macrophages (Wojcik et al., 2008). ABCG4 is
highly expressed in the brain, and the Abcg4 -/-mouse has abnormal sterol efflux in the brain (Annilo et al., 2001; Wang
et al., 2008).
Several ABCB family half transporters proteins localize to the
mitochondria, and their functions were elucidated from mouse models. InAbcb6 -/- mice, the gene is expressed in the
mitochondria and transport coproporphyrin III into the mitochondria
(Ulrich et al., 2012). The ABCB8 protein localizes to the mitochondria,
and Abcb8 disruption leads to defects in mitochondrial iron
export, cytosolic Fe/S protein levels, and cardiomyopathy (Ichikawa et
al., 2012). In addition, disruption of Abcb10 leads to a lack of heme
biosynthesis and erythropoiesis (Yamamoto et al., 2014).
In summary, for nearly all the human ABC genes causing Mendelian
disorders, the mouse knockout strains recapitulate one or more
phenotypes and serve as valuable models for further studies and
development of therapeutics. In addition, the disruption of mouse ABC
genes of unknown function has ascribed multiple cellular transport
properties to several transporters, leading to extensive new knowledge
on the full spectrum of ABC transporter efflux properties.