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At least 19 recordsLinked to original sources
PubMed2000

Cysteine residues in the C-terminus of the neutral- and basic-amino-acid transporter heavy-chain subunit contribute to functional properties of the system b(0,+)-type amino acid transporter.

The neutral- and basic-amino-acid-transport glycoprotein NBAT (rBAT, D2) expressed in renal and jejunal brush-border membranes interacts with the b(0,+)AT permease to produce a heteromeric transporter effecting amino acid and cystine absorption. NBAT mutations result in type I cystinuria. The b(0,+)AT permease is presumed to be the catalytic subunit, but we have been investigating the possibility that cysteine residues within the C-terminus of NBAT are also important for expression of transport function. NBAT mutants were produced with combinations of Cys(664/671/683)-->Ala substitutions. Mutants with Cys(664)-->Ala show decreased arginine and cystine transport and specifically lose sensitivity to inhibition of transport by the thiol-group reagent N-ethylmaleimide (NEM). We suggest that the C-terminus of NBAT may have a direct role in the mechanism of System b(0,+) transport (the major transport activity defective in type I cystinuria) and that Cys(664) of NBAT is the major target for NEM-induced inactivation of the transport mechanism.

Amino Acid Sequence↗
PubMed2000

Transport properties of a system y+L neutral and basic amino acid transporter. Insights into the mechanisms of substrate recognition.

The properties of system y(+)L-mediated transport were investigated on rat system y(+)L transporter, ry(+)LAT1, coexpressed with the heavy chain of cell surface antigen 4F2 in Xenopus oocytes. ry(+)LAT1-mediated transport of basic amino acids was Na(+)-independent, whereas that of neutral amino acids, although not completely, was dependent on Na(+), as is typical of system y(+)L-mediated transport. In the absence of Na(+), lowering of pH increased leucine transport, without affecting lysine transport. Therefore, it is proposed that H(+), besides Na(+) and Li(+), is capable of supporting neutral amino acid transport. Na(+) and H(+) augmented leucine transport by decreasing the apparent K(m) values, without affecting the V(max) values. We demonstrate that although ry(+)LAT1-mediated transport of [(14)C]l-leucine was accompanied by the cotransport of (22)Na(+), that of [(14)C]l-lysine was not. The Na(+) to leucine coupling ratio was determined to be 1:1 in the presence of high concentrations of Na(+). ry(+)LAT1-mediated leucine transport, but not lysine transport, induced intracellular acidification in Chinese hamster ovary cells coexpressing ry(+)LAT1 and 4F2 heavy chain in the absence of Na(+), but not in the presence of physiological concentrations of Na(+), indicating that cotransport of H(+) with leucine occurred in the absence of Na(+). Therefore, for the substrate recognition by ry(+)LAT1, the positive charge on basic amino acid side chains or that conferred by inorganic monovalent cations such as Na(+) and H(+), which are cotransported with neutral amino acids, is presumed to be required. We further demonstrate that ry(+)LAT1, due to its peculiar cation dependence, mediates a heteroexchange, wherein the influx of substrate amino acids is accompanied by the efflux of basic amino acids.

Amino Acid Transport Systems, Basic↗
PubMed1996

rBAT is an amino acid exchanger with variable stoichiometry.

The rBAT protein, when expressed in Xenopus oocytes, was previously shown to reproduce the selectivity of the Na(+)-independent neutral and basic amino acid transport system called bo,+. More recently, the capacity of rBAT to generate a transmembrane current was demonstrated when addition of neutral amino acids stimulated the efflux of cations (presumably basic amino acids) in rBAT-injected oocytes. In the present paper, aminoisobutyric acid (AIB), a neutral amino acid analogue, was shown to induce outward currents (efflux of basic amino acids) through rBAT similar to those caused by alanine in terms of affinity, maximal currents and I-V curves. Despite generating similar currents, the AIB transport rate was more than 30 times lower than that of alanine, thus challenging the assumption that rBAT functions as a classical exchanger. Experiments using a cut-open oocyte voltage clamp demonstrated that AIB was capable of stimulating rBAT-mediated currents from either side of the membrane. AIB, like alanine, was able to stimulate the efflux of radiolabeled alanine and arginine while no rBAT-mediated efflux was measurable in the absence of external rBAT substrates. These results demonstrate that (i) the presence of amino acids is required on both sides of the membrane for rBAT to mediate amino acid flux and thus rBAT must be some type of exchanger but (ii) rBAT-mediated amino acid influx is not stoichiometrically related to the efflux. A model of a "double gated pore" is proposed to account for these properties of rBAT, which contravene standard models of exchangers and other transporters.

Alanine↗
PubMed2002

Low and high affinity amino acid H+-cotransporters for cellular import of neutral and charged amino acids.

Amides and acidic amino acids represent the major long distance transport forms of organic nitrogen. Six amino acid permeases (AAPs) from Arabidopsis mediating transport of a wide spectrum of amino acids were isolated. AAPs are distantly related to plasma membrane amino acid transport systems N and A and to vesicular transporters such as VGAT from mammals. A detailed comparison of the properties by electrophysiology after heterologous expression in Xenopus oocytes shows that, although capable of recognizing and transporting a wide spectrum of amino acids, individual AAPs differ with respect to specificity. Apparent substrate affinities are influenced by structure and net charge and vary by three orders of magnitude. AAPs mediate cotransport of neutral amino acids with one proton. Uncharged forms of acidic and basic amino acids are cotransported with one proton. Since all AAPs are differentially expressed, different tissues may be supplied with a different spectrum of amino acids. AAP3 and AAP5 are the only transporters mediating efficient transport of the basic amino acids. In vivo competition shows that the capability to transport basic amino acids in planta might be overruled by excess amides and acidic amino acids in the apoplasm. With the exception of AAP6, AAPs do not recognize aspartate; only AAP6 has an affinity for aspartate in the physiologically relevant range. This property is due to an overall higher affinity of AAP6 for neutral and acidic amino acids. Thus AAP6 may serve a different role either in cooperating with the lower affinity systems to acquire amino acids in the low concentration range, as a system responsible for aspartate transport or as an uptake system from the xylem. In agreement, a yeast mutant deficient in acidic amino acid uptake at low aspartate concentrations was complemented only by AAP6. Taken together, the AAPs transport neutral, acidic and cationic amino acids, including the major transport forms, i.e. glutamine, asparagine and glutamate. Increasing proton concentrations strongly activate transport of amino acids. Thus the actual apoplasmic concentration of amino acids and the pH will determine what is transported in vivo, i.e. major amino acids such as glutamine, asparagine, and glutamate will be mobilized preferentially.

Algorithms↗
PubMed1997

Cloning, functional expression and dietary regulation of the mouse neutral and basic amino acid transporter (NBAT).

The Na+-independent dibasic and neutral amino acid transporter NBAT is among the least hydrophobic of mammalian amino acid transporters. The transporter contains one to four transmembrane domains and induces amino acid transport activity via a b0,+-like system when expressed in Xenopus oocytes. However, the physiological role of NBAT remains unclear. Complementary DNA clones encoding mouse NBAT have now been isolated. The expression of mouse NBAT in Xenopus oocytes also induced an obligatory amino acid exchange activity similar to that of the b0,+-like system. The amount of NBAT mRNA in mouse kidney increased during postnatal development, consistent with the increase in renal cystine and dibasic transport activity. Dietary aspartate induced a marked increase in cystine transport via the b0,+ system in mouse ileum. A high-aspartate diet also increased the amount of NBAT mRNA in mouse ileum. In the ileum of mice fed on the aspartate diet, the extent of cystine transport was further increased by preloading brush border membrane vesicles with lysine. Hybrid depletion of NBAT mRNA from ileal polyadenylated RNA revealed that the increase in cystine transport activity induced by the high-aspartate diet, as measured in Xenopus oocytes, was attributable to NBAT. These results demonstrate that mouse NBAT has an important role in cystine transport.

Amino Acid Sequence↗
PubMed1993

Characterization of the rat neutral and basic amino acid transporter utilizing anti-peptide antibodies.

High-titer, site-specific antibodies have been produced against the rat kidney broad-spectrum, sodium-independent neutral and basic amino acid transporter (NBAA-Tr) whose cDNA we cloned earlier. These antibodies have allowed us to characterize the transporter protein in normal rat tissues and in various cellular and in vitro expression systems. Western analysis detected 84- to 87-kDa glycosylated species enriched in rat renal and jejunal epithelial cell brush border membranes. In vitro translation of NBAA-Tr complementary RNA in the rabbit reticulocyte lysate system yielded a 78-kDa protein, a molecular mass that was predicted by the amino acid sequence deduced from the cloned cDNA. Translation in the presence of rough microsomal membranes yielded a glycosylated 89-kDa species. Glycosylated 87- to 89-kDa species were also expressed in Xenopus oocytes microinjected with NBAA-Tr complementary RNA and in COS-7 cells transfected with NBAA-Tr cDNA. Localization of NBAA-Tr in renal and intestinal brush border membranes is consistent with its proposed role in transepithelial transport of amino acids.

Amino Acid Sequence↗
PubMed1999

Interactions between the thiol-group reagent N-ethylmaleimide and neutral and basic amino acid transporter-related amino acid transport.

The neutral and basic amino acid transport protein (NBAT) expressed in renal and jejunal brush-border membranes is involved in amino acid and cystine absorption. NBAT mutations result in Type 1 cystinuria. A C-terminal myc-tagged NBAT (NBATmyc) retains the amino acid transport and protein-protein interaction properties of NBAT when expressed in Xenopus oocytes. Neutral amino acid (Ala, Phe)-cationic amino acid (Arg) heteroexchanges related to NBATmyc expression in oocytes are inactivated by treatment with the thiol-group reagent N-ethylmaleimide (NEM), although significant Arg-Arg and Ala-Ala homoexchanges persist. Inactivation of heteroexchange activity by NEM is accompanied by loss of >85% of alanine and cystine uptake, with smaller (<50%) inhibition of arginine and phenylalanine uptake. NEM-sensitive cystine uptake and arginine-alanine heteroexchange (system b(0,+) activity) are not expressed by an NBAT truncation mutant (NBATmyc-Sph1) lacking the 13 C-terminal amino acid residues, but the mutant expresses NEM-resistant transport activity (system y(+)L-like) equivalent to that of full-length NBATmyc. The deleted region of NBATmyc-Sph1 contains two cysteine residues (671/683) which may be the targets of NEM action. The synthetic amino acid 2-trifluoromethylhistidine (TFMH) stimulated alanine efflux at pH 7.5 and arginine at pH 5.5, but not vice versa, establishing the existence of distinct pathways for cationic and neutral amino acid homoexchange (TFMH is zwitterionic at pH 7.5 and cationic at pH 5.5). We suggest that NBAT expresses a combination of system b(0,+) and y(+)L-like activities, possibly by interacting with different light-chain subunits endogenous to oocytes (as does the homologous 4F2hc protein). The C-terminus of NBAT may also have an additional, direct role in the mechanism of System b(0,+) transport (the major transport activity that is defective in Type 1 cystinuria).

Amino Acid Sequence↗
PubMed1995

Oligomeric structure of a renal cystine transporter: implications in cystinuria.

Homologous proteins (NBAT) which mediate sodium-independent transport of neutral as well as basic amino acids and cystine when expressed in Xenopus oocytes were recently cloned from mammalian kidneys. Mutations in human NBAT have been implicated in cystinuria. Here, we show that rat kidney and jejunal brush border membrane NBAT (85 kDa) is found in association with a 50 kDa protein. The association involves one or more interprotein disulfide bonds. Rabbit kidney brush border membranes and membranes of NBAT cRNA-injected Xenopus oocytes also contain such heterodimers. Our data suggest that the heterodimer is the minimal functional unit of NBAT-mediated amino acid transport and that the NBAT-associated 50 kDa protein could play a role in cystinuria.

Amino Acid Transport Systems, Basic↗
PubMed2001

Identification of differentially expressed genes in rat hippocampus after transient global cerebral ischemia using subtractive cDNA cloning based on polymerase chain reaction.

BACKGROUND AND PURPOSE: The purpose of this study is to identify new molecules that play important roles in the phenomena that occur in the hippocampus after transient global cerebral ischemia, as clues to better understanding of the mechanisms. METHODS: A subtractive cDNA library was established by suppression subtractive hybridization of rat hippocampal tissues after transient global cerebral ischemia. With differential screening of the library, upregulated fragments were identified. The mRNA expression levels of selected genes were measured with semiquantitative reverse transcriptase polymerase chain reaction (PCR). RESULTS: Among more than 100 isolated fragments, approximately half were determined to be identical to known sequences. The rest showed high homology to known sequences, and only 2 did not exhibit homology to any known sequences. The expression of 5 genes identified in this study increased in 24 hours after ischemia to a level twice as high as that in sham-operated controls. These included furin, prosaposin, synaptotagmin IV, heat shock protein 105, and the neutral and basic amino acid transporter (NBAT). The increases in the mRNA expression levels of the genes except NBAT, as revealed by semiquantitative reverse transcription PCR, were statistically significant at both 6 and 24 hours after ischemia. CONCLUSIONS: Genes isolated are thought to be associated with production of proteins necessary for degeneration, neuroprotection, and reconstruction of neurons. How the expression of these genes relates to functional changes after ischemia remains to be determined. PCR-based subtractive cDNA cloning is demonstrated to be a useful tool for analyzing in vivo gene expression in animal ischemia models.

Amino Acid Transport Systems, Basic↗
PubMed1994

Characterization of the promoter region of the gene for the rat neutral and basic amino acid transporter and chromosomal localization of the human gene.

The promoter region of the rat kidney neutral and basic amino acid transporter (NBAT) gene has been isolated and sequenced. The major transcription initiation site was mapped by primer extension. The entire promoter region and a set of 5' deletions within it were expressed at a high level in LLC-PK1 cells using the luciferase indicator gene. Positive and negative regulatory elements in the promoter region were observed. A human genomic clone of the transporter was also obtained and was used to localize the NBAT gene at the p21 region of chromosome 2.

Amino Acid Sequence↗
PubMed1996

Multiple components of arginine and phenylalanine transport induced in neutral and basic amino acid transporter-cRNA-injected Xenopus oocytes.

The induced uptakes of L-[3H]phenylalanine and L-[3H]arginine in oocytes injected with clonal NBAT (neutral and basic amino acid transporter) cRNA show differential inactivation by pretreatment with N-ethylmaleimide (NEM), revealing at least two distinct transport processes. NEM-resistant arginine transport is inhibited by leucine and phenylalanine but not by alanine or valine; mutual competitive inhibition of NEM-resistant uptake of arginine and phenylalanine indicates that the two amino acids share a single transporter. NEM-sensitive arginine transport is inhibited by leucine, phenylalanine, alanine and valine. At least two NEM-sensitive transporters may be expressed because we have been unable to confirm mutual competitive inhibition between arginine and phenylalanine transport. The NEM-resistant transport mechanism appears to involve distinct but overlapping binding sites for cationic and zwitterionic substrates. NBAT is known to form oligomeric protein complexes in cell membranes, and its functional roles when expressed in Xenopus oocytes may include interaction with oocyte proteins, leading to increased native amino acid transport activities; these resemble NBAT-expressed activities in terms of NEM-sensitivity and apparent substrate range (including an unusual inhibition by beta-phenylalanine.

Amino Acid Transport Systems, Basic↗
PubMed1993

Ultrastructural localization of a neutral and basic amino acid transporter in rat kidney and intestine.

A sodium-independent neutral and basic amino acid transporter (NBAT) from rat kidney was recently cloned and its amino acid sequence deduced. We used light and electron microscopic immunoperoxidase labeling to determine the cellular localization of NBAT in rat kidney and small intestine. The localization was carried out using site-directed antisera raised against synthetic peptides within NBAT. The most prominent localization of NBAT was in microvilli of epithelial cells lining renal proximal tubules. Microvilli of small intestinal epithelia were less frequently immunoreactive. Unexpectedly, the most intense labeling in the small intestine was seen within enteroendocrine cells and submucosal neurons. The neuronal labeling was highly localized within dense core vesicles in axon terminals apposed to the basal lamina near fenestrated blood vessels. These results support the proposal that NBAT plays a role in reabsorption of amino acids in renal tubules. In addition, they suggest that NBAT (or NBAT-like proteins) may have multiple functions in the small intestine, including luminal uptake of amino acids and vesicular uptake of related substrates into enteroendocrine cells and enteric neurons.

Amino Acid Sequence↗
PubMed1994

Membrane topology of the rat kidney neutral and basic amino acid transporter.

A recently cloned rat kidney protein (NBAT) mediates the sodium-independent transport of neutral as well as basic amino acids and cystine when expressed in Xenopus laevis oocytes. The human equivalent of this transporter may be the one that is defective in cystinuria. Immunocytochemical studies have indicated that NBAT is primarily localized in the brush border membranes of rat kidney and intestinal epithelial cells, a localization consistent with its proposed role in amino acid transport. Two contrasting topological models have been proposed for NBAT: a four membrane-spanning domain (MSD) Nin-Cin model and a single MSD Nin-Cout model. We have investigated the topology of this membrane protein using two different approaches. One method was an immunofluorescent labeling technique in which intact or membrane-permeabilized cells expressing NBAT were probed with antibodies directed against putative extracellular and intracellular domains of the protein. In the second method, fragments generated by limited surface proteolysis of intact brush border membrane vesicles were subjected to immunoblot analysis using several site-specific antibodies. Both approaches yielded results consistent with a four MSD Nin-Cin topological model for NBAT.

Amino Acid Sequence↗
PubMed1995

Sodium-independent currents of opposite polarity evoked by neutral and cationic amino acids in neutral and basic amino acid transporter cRNA-injected oocytes.

To elucidate the electrical events associated with the movement of amino acids by the neutral and basic amino acid transporter (NBAT)-encoded protein (Yan, N., Mosckovitz, R., Gerber, L.D., Mathew, S., Murty, V.V. V.S., Tate, S.S., and Udenfriend, S. (1994) Proc. Natl. Acad. Sci. USA 91, 7548-7552), we have investigated the membrane potential and current changes associated with the increased transport of amino acids across the cell membrane of NBAT cRNA-injected Xenopus laevis oocytes. Superfusion of 0.05 mM L-phenylalanine, in current-clamped NBAT-injected oocytes, caused a hyperpolarization (8.5 +/- 0.9 mV), but superfusion of L-arginine caused a depolarization (18.3 +/- 1.3 mV). In voltage-clamped (-60 mV) oocytes, superfusion of L-phenylalanine evoked a sodium- and chloride-independent, saturable (Km = 0.34 +/- 0.02 mM, Imax = 31.3 +/- 0.5 nA), outward current. This outward current was reduced in the presence of high external [K] and was barium-sensitive. Outward currents were also evoked by L-leucine, L-glutamine, L-alanine, D-phenylalanine, and L-beta-phenylalanine. Superfusion of L-arginine evoked a saturable (Km = 0.09 +/- 0.02 mM, Imax = -29.2 +/- 1.3 nA) inward current; L-lysine and D-arginine also evoked inward currents. L-Glutamate and beta-alanine failed to evoke any currents. Effluxes of L-[3H]phenylalanine and L-[3H]arginine were trans-stimulated in the presence of either amino acid. Flux-current comparisons indicated amino acid:charge movement stoichiometry of 1:1 for both neutral and cationic amino acids. These findings indicate that the amino acid transport activity(ies) expressed in NBAT cRNA-injected oocytes is electrogenic by a mechanism including the outward movement of a net positive charge (potassium ion or cationic amino acid) in exchange for uptake of a neutral amino acid.

Amino Acid Transport Systems, Basic↗
PubMed1997

Electrogenic L-histidine transport in neutral and basic amino acid transporter (NBAT)-expressing Xenopus laevis oocytes. Evidence for two functionally distinct transport mechanisms induced by NBAT expression.

We have investigated the neutral and basic amino acid transporter (NBAT)-induced transport of L-histidine in Xenopus laevis oocytes. Transport of L-histidine (pH 7.5) was electrogenic and Na+-dependent with a 14-fold increase in L-histidine- (1 mM) evoked current (I(His) = -14.7 +/- 1.5 nA) in NBAT-expressing oocytes compared with native (water-injected or uninjected) oocytes (-1.0 +/- 0.2 nA); the Na+-dependent histidine transport showed a stoichiometry of 1:1 (histidine:sodium). I(His) was stereospecific at pH 7.5 and saturable in both NaCl and tetramethylammonium chloride media. L-Histidine (1 mM) at pH 8.5, at which histidine is uncharged, evoked an Na+-independent outward current (11 +/- 1.2 nA) in NBAT-expressing oocytes. The total inward 0.1 mM I(His) increased from -9 +/- 0.8 nA at pH 7.5 to -19 +/- 2.6 nA at pH 6.5, at which histidine is predominantly cationic. The increase in I(His) from pH 7.5 to 6.5 was found to be almost entirely due to the Na+-independent component. At pH 7.5, L-histidine weakly inhibited the Na+-independent L-arginine uptake; however, this inhibition was much stronger (>90%) at pH 6.5. L-Histidine transport, at pH 7.5, is stimulated by NBAT expression, but unlike L-phenylalanine or L-arginine transport, L-histidine transport is Na+-dependent and stereoselective. The induction of Na+-dependent L-histidine transport in NBAT-expressing oocytes provides new evidence that NBAT stimulates functionally distinct amino acid transporters including Na+-dependent L-histidine and Na+-independent L-arginine and L-phenylalanine transporters. The parallel induction of two different mechanisms argues that NBAT is not an amino acid transporter itself but, instead, is a transport-activating protein for a range of amino acid translocases.

Amino Acid Transport Systems, Basic↗
PubMed1999

Regional and subcellular distribution of a neutral and basic amino acid transporter in forebrain neurons containing nitric oxide synthase.

The neutral and basic amino acid transporter (NBAT) facilitates sodium-independent transport of L-amino acids in renal and intestinal epithelial cells and has been postulated to play a similar role in neurons. In previous studies, NBAT has been detected within enteric and brainstem autonomic neurons in a distribution similar to that of constitutive nitric oxide synthase (cNOS). Furthermore, L-arginine, the required precursor for nitric oxide synthesis, is an excellent NBAT substrate. Together, these findings suggest that NBAT may play a role in the regulation of nitric oxide synthesis, through the control of precursor availability. To gain insight into the potential physiological role of NBAT in central neurons, we used an antipeptide antiserum to examine the light and electron microscopic immunocytochemical localization of NBAT in the rat forebrain and to compare this distribution with that of cNOS. Immunolabeling for NBAT was detected within perikarya and dendrite-like processes that were most numerous in the frontal and cingulate cortex, the ventral striatum, the central amygdala, and the bed nucleus of the stria terminalis. Labeled varicose axonal processes were distributed most densely in the agranular insular cortex and the paraventricular nuclei of the thalamus and hypothalamus (PVH). Electron microscopy showed that immunogold labeling for NBAT was distributed along plasmalemmal and vacuolar membranes within somata, dendrites, and axonal profiles. Many of the NBAT-containing somata and dendrites contained detectable cNOS. Our results suggest that expression of NBAT may provide specific populations of cNOS-containing forebrain neurons with a unique mechanism for regulating somatodendritic synthesis of nitric oxide.

Amino Acid Transport Systems, Basic↗
PubMed1995

Immunocytochemical localization of the renal neutral and basic amino acid transporter in rat adrenal gland, brainstem, and spinal cord.

A neutral and basic amino acid transporter (NBAT) cloned from rat kidney was recently localized to enteroendocrine cells and enteric neurons. We used an antibody directed against a synthetic peptide representing a putative extracellular domain of NBAT to determine whether this transporter was also present in other endocrine and neural tissues, including rat adrenal gland, brainstem, and spinal cord. Abundant, highly granular labeling for NBAT was observed in the cytoplasm of chromaffin and ganglion cells in the adrenal medulla. A small population of intensely labeled varicose processes was also seen in both the cortex and the medulla of the adrenal gland. More numerous, intensely labeled varicose processes were detected in brainstem and spinal cord nuclei, including the locus coeruleus, rostral ventrolateral medulla, nuclei of the solitary tract, dorsal motor nucleus of the vagus, and intermediolateral cell column of the thoracic spinal cord. Significant perikaryal labeling for NBAT was only detected in brainstem and spinal cord following intraventricular colchicine treatment, which increased the number, distribution, and intensity of NBAT-immunolabeled cells. These NBAT-immunoreactive perikarya were most numerous in the locus coeruleus, rostral ventrolateral medulla, nuclei of the solitary tract, and raphe nuclei. Ultrastructural examination of the nuclei of the solitary tract of normal rats showed that NBAT was localized predominantly to axon terminals. Within these labeled terminals, NBAT was associated with large dense core vesicles and discrete segments of plasma membrane. The observed localization of NBAT suggests that this renal specific amino acid transporter subserves a role as a vesicular or plasmalemmal transporter in monoamine-containing cells, including chromaffin cells and autonomic neurons.

Adrenal Medulla↗
PubMed2005

Intrachromosomal serial replication slippage in trans gives rise to diverse genomic rearrangements involving inversions.

Serial replication slippage in cis (SRScis) provides a plausible explanation for many complex genomic rearrangements that underlie human genetic disease. This concept, taken together with the intra- and intermolecular strand switch models that account for mutations that arise via quasipalindrome correction, suggest that intrachromosomal SRS in trans (SRStrans) mediated by short inverted repeats may also give rise to a diverse series of complex genomic rearrangements. If this were to be so, such rearrangements would invariably generate inversions. To test this idea, we collated all informative mutations involving inversions of >or=5 bp but <1 kb by screening the Human Gene Mutation Database (HGMD; www.hgmd.org) and conducting an extensive literature search. Of the 21 resulting mutations, only two (both of which coincidentally contain untemplated additions) were found to be incompatible with the SRStrans model. Eighteen (one simple inversion, six inversions involving sequence replacement by upstream or downstream sequence, five inversions involving the partial reinsertion of removed sequence, and six inversions that occurred in a more complicated context) of the remaining 19 mutations were found to be consistent with either two steps of intrachromosomal SRStrans or a combination of replication slippage in cis plus intrachromosomal SRStrans. The remaining lesion, a 31-kb segmental duplication associated with a small inversion in the SLC3A1 gene, is explicable in terms of a modified SRS model that integrates the concept of "break-induced replication." This study therefore lends broad support to our postulate that intrachromosomal SRStrans can account for a variety of complex gene rearrangements that involve inversions.

Amino Acid Transport Systems, Basic↗