Human Molecular Genetics, 2001, Vol. 10, No. 2 153-161
© 2001 Oxford University Press
Targeted disruption of mouse Pds provides insight about the inner-ear defects encountered in Pendred syndrome
1Genome Technology Branch, 5Embryonic Stem Cell/Transgenic Mouse Core and 6Office of Laboratory Animal Medicine, National Human Genome Research Institute and 2Laboratory of Cellular Biology, 3Laboratory of Molecular Genetics and 4Laboratory of Molecular Biology, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA
Received 9 November 2000; Accepted 15 November 2000.
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ABSTRACT |
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Following the positional cloning of PDS, the gene mutated in the deafness/goitre disorder Pendred syndrome (PS), numerous studies have focused on defining the role of PDS in deafness and PS as well as elucidating the function of the PDS-encoded protein (pendrin). To facilitate these efforts and to provide a system for more detailed study of the inner-ear defects that occur in the absence of pendrin, we have generated a Pds-knockout mouse. Pds–/– mice are completely deaf and also display signs of vestibular dysfunction. The inner ears of these mice appear to develop normally until embryonic day 15, after which time severe endolymphatic dilatation occurs, reminiscent of that seen radiologically in deaf individuals with PDS mutations. Additionally, in the second postnatal week, severe degeneration of sensory cells and malformation of otoconia and otoconial membranes occur, as revealed by scanning electron and fluorescence confocal microscopy. The ultrastructural defects seen in the Pds–/– mice provide important clues about the mechanisms responsible for the inner-ear pathology associated with PDS mutations.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Pendred syndrome (PS) is an autosomal recessive disorder characterized by sensorineural deafness and goitre. The hearing loss is generally profound and prelingual, although occasionally it is later in onset and progressive (1–5), with such cases often associated with mild head trauma. The majority of PS patients also have radiologically detectable structural malformations of the inner ear, the most common feature of which is an enlarged vestibular aqueduct/endolymphatic duct (4,6–8). Less commonly, a full Mondini malformation is present (4,6,9) where the apical two turns of the cochlea are merged into a common cavity. The goitre in PS is even more variable in its presentation; it can develop at any age (although generally after puberty), but may be totally absent in some affected individuals. As a useful diagnostic tool, the thyroid disease in PS is generally associated with an abnormal release of iodide from the thyroid during a perchlorate discharge test (10).
For just over 100 years after Vaughan Pendred’s original description of the syndrome in 1896 (11), the aetiology of PS remained largely unknown. In 1997, we identified the gene (PDS) defective in PS by a positional cloning strategy (12). This finding immediately launched a number of studies investigating PDS structure, expression and function, including those aiming to establish how defects in one gene can lead to the distinct phenotypic features involving the inner ear and thyroid. PDS encodes the protein pendrin and is expressed in thyroid, inner ear and kidney (12). Pendrin belongs to a large family of anion transporters (12) and, in heterologous expression systems, has been shown to transport iodide, chloride (13), formate and nitrate (14).
The demonstration of pendrin’s iodide-transporting capability (14) coupled with the thyroid dysfunction associated with PS pointed to a likely role for pendrin in the thyroid. Specifically, iodide is taken up by the thyroid via the sodium/iodide symporter in the basolateral membrane of follicular thyrocytes. Subsequently, the iodide is transported across the thyrocyte’s apical membrane into the colloid and is then incorporated into thyroglobulin. Perchlorate, which inhibits the function of the sodium/iodide symporter, causes the leakage of any free iodide back into the bloodstream. Thus, in PS patients, the partial release of radiolabelled iodide during a perchlorate discharge test indicates that iodide uptake by the thyrocyte is normal, but that there is a defect in its transport across the apical membrane or its incorporation into thyroglobulin. Our immunolocalization studies demonstrated that pendrin resides within the apical membrane of thyrocytes (15), thereby suggesting that the protein functions as an apical porter of iodide in the thyroid. The goitre encountered in PS is presumably a consequence of a reactive hyperplasia counteracting the defect in this transport function.
The precise role of pendrin in the inner ear is presently less well defined. Following our isolation and characterization of the murine and rat Pds orthologues (16), we performed mRNA in situ hybridization to examine Pds expression in the mouse inner ear (16). These studies revealed that Pds is expressed in several discrete areas of the inner ear that are putatively important in the regulation of endolymphatic fluid composition, consistent with pendrin’s anion transport role. Of note, these data provided evidence directly implicating the absence of pendrin in the inner ear as the cause of deafness in PS, thereby helping to dispel the theory that the deafness is secondary to fetal hypothyroidism [a known cause of deafness associated with ultrastructural cochlear malformations (17–20)].
In parallel with the above functional studies, detailed mutational analyses of the PDS gene have revealed a large set of deafness-associated mutations (3,4,7,21–30). Some of these studies (7,21) reported mutations in patients with deafness and large vestibular aqueducts but no goitre. The identification of PDS mutations in families without goitre indicates that defects in the gene account for a broader spectrum of deafness than just PS, which is believed to be one of the most common forms of syndromic deafness (31). In addition, while a genetic background or environmental effect must contribute to the variable phenotypic expressivity in individuals from the same PS family, it would also appear that some PDS mutations truly result in non-syndromic deafness. The latter notion is supported by both the occurrence of specific PDS mutations in deaf patients without goitre (7,21) and the presence of residual pendrin function associated with some of these mutations (32).
Although our understanding of the PDS gene and pendrin has advanced tremendously in the past few years, many important studies, especially those aimed at unravelling the inner-ear pathology associated with PDS mutations, require a model experimental system. Here we report the generation of a Pds-knockout mouse. Characterization of Pds–/– mice, including detailed ultrastructural studies of their inner ears, has provided important clues about the aetiology of deafness in PS.
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RESULTS |
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Vestibular and auditory dysfunction of Pds–/– mice
A gene-targeting approach was used to generate a Pds-knockout allele and subsequent Pds–/– mice (Fig. 1). Pds+/– x Pds+/– matings yielded offspring with genotypes of the expected ratio of
1:2:1 (93 Pds+/+:233 Pds+/–:94 Pds–/–).
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Pds–/– mice appear normal at birth. However, when beginning to walk, many Pds–/– mice show considerable unsteadiness compared with normal littermates. By 3 weeks, these signs are often replaced by profound circling behaviour (Fig. 2A–C) and/or pronounced head tilting (Fig. 2D and E) and bobbing as well as an abnormal reaching response (Fig. 2F). Representative video clips showing the vestibular dysfunction of Pds–/– mice are available at http://genome.nhgri.nih.gov/pdsko . Interestingly, the vestibular disease shows variable expressivity with respect to its presence, features and severity (but not age of onset). For a given mouse, the vestibular signs (or lack thereof) are generally stable over time, including the direction of head-tilt or circling. The variable vestibular phenotype was quantitatively documented by rotorod testing (33), which measures the ability of an animal to balance on a rotating rod. Pds–/– animals collectively performed worse than their Pds+/– and Pds+/+ littermates (Fig. 2G). Furthermore, Pds–/– mice without vestibular signs performed better as a group than those with severe vestibular signs.
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Pds–/– mice fail to exhibit a Preyer’s reflex to a loud clap, strongly implying profound hearing loss. Formal hearing assessment was performed by auditory-evoked brainstem response analyses. Pds+/+ and Pds+/– mice returned normal waveforms and thresholds, suggesting an intact auditory system. Conversely, Pds–/– animals showed no characteristic waveforms at intensities up to 100 dB sound pressure level (SPL) and with all four stimuli tested, indicating the complete absence of hearing (Fig. 3).
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Inner-ear anatomy of Pds–/– mice
To investigate the vestibular and auditory defects seen in Pds–/– mice, we examined their inner-ear anatomy at various developmental stages. The gross anatomy of inner ears from prenatal and newborn mice was analysed by injecting a latex paint solution into the lumen of the membranous labyrinth. No obvious anatomical defects are evident in Pds–/– mice until embryonic day (E)15; at this stage, the membranous labyrinth is relatively mature (34) (Fig. 4A). These results correlate well with the finding that inner-ear Pds expression does not occur until E13 (16). At E15, the inner ears of Pds–/– mice began to develop a dilated endolymphatic duct and sac (Fig. 4B). Starting at E15.5–16.5, the cochlea and saccule also become dilated (Fig. 4D and E), as do the semicircular canals in some cases (Fig. 4E). Histological studies at postnatal day (P)1 confirm the presence of an enlarged endolymphatic duct and sac (compare Fig. 4G and F) as well as a bulging Reissner’s membrane in the cochlea due to dilatation of the scala media (compare Fig. 4I and H). The dilated nature of the membranous labyrinth is even more pronounced in the inner ears of adult Pds–/– mice (Fig. 5B and C).
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To gain additional insight about the sensory deficits in Pds–/– mice, ultrastructural examination of their inner ears was performed. Scanning electron microscopy studies of adult mice revealed evidence for degeneration of the sensory cells of the inner ear (Figs 5 and 6). In the organ of Corti, the outer hair cells are severely affected, albeit with considerable variation among different cochleas as well as areas of the same cochlea (Fig. 6B–D). The inner hair cells also show varying extents of degeneration (Fig. 6B–D), in some cases associated with enlarged sterocilia (Fig. 6B). In the utricle and saccule, degeneration of the maculae is evident (Fig. 5). Most striking is the almost complete absence of otoconia (Fig. 5C), with the occasional presence of giant otoconia (Fig. 5B; also compare Fig. 5E with D). However, the underlying layers are also affected, with destruction of the otoconial membrane (compare Fig. 5G and F) and patchy degeneration of the hair cells beneath (compare Fig. 5I and H). Importantly, examination of younger Pds–/– mice revealed that normally developed sensory hair cells of the cochlea and vestibular maculae are actually present at P7 (Fig. 7A and D). By P15, there is clear evidence of degeneration of these structures (Fig. 7B and E), which progressively worsens through P45 (Fig. 7C and F).
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Thyroid histology and function of Pds–/– mice
Pds–/– mice do not show any signs of overt hypothyroidism at any age up to 2 years. Neither macroscopic nor microscopic studies of thyroids from Pds–/– mice reveal any pathology; thyroids of Pds–/– and Pds+/+ mice are identical in size and histology. Additionally, standard serum thyroid (as well as renal) function tests are normal in Pds–/– mice. Thus, at least in the genetic background examined (129Sv/Ev), Pds–/– mice resemble patients with non-syndromic deafness associated with PDS mutations (i.e. they lack evidence of thyroid disease).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The development of a Pds-knockout mouse is providing important insight into the role of pendrin in the developing inner ear. Pds–/– mice develop early-onset, profound deafness, and thus appear to provide a valuable model for studying the auditory dysfunction associated with PDS mutations. Additionally, these animals show pronounced signs of vestibular disease. This is not entirely unexpected since some PS patients occasionally complain of vestibular symptoms (5,35), with a larger fraction having evidence of vestibular dysfunction by caloric testing (1,36,37) and the severity being highly variable (as with Pds–/– mice). It is well documented that vestibular dysfunction in mouse models of human deafness (e.g. shaker-1 and shaker-2) is often more pronounced than in the human condition (38–41); however, the unusual feature of our mouse model is the variable expressivity of the vestibular signs. As fully inbred Pds–/– mice (in a 129Sv/Ev background) display the same variability in vestibular phenotype as their outbred counterparts, as this variability is the same among littermates as among non-littermates derived from identical (or different) parents, and as the unidirectional nature of the vestibular signs in a given mouse suggests laterality differences, a non-genetic factor(s) is probably responsible for the ultimate phenotype. One should also note that as Pds–/– mice show no biochemical or histological evidence of thyroid disease, differences in thyroid function do not account for the variable presence of vestibular signs.
The lack of pendrin in Pds–/– mice leads to a profound dilatation of inner-ear structures. One can postulate that this is secondary to an altered osmotic environment of the endolymph caused by the absence of the protein’s anion-transporting function, as we previously discussed (16). This endolymphatic swelling appears to be analogous to the malformations detected radiologically in PS patients, particularly the enlarged vestibular aqueduct (the structure housing the endolymphatic duct). It is interesting to note that, until now, the PS-associated anatomical defects (specifically, enlarged vestibular aqueducts and the Mondini malformation), have been attributed to a developmental-arrest process because the resulting structures are reminiscent of a 7-week human embryonic inner ear (42). However, our results with Pds–/– mice reveal that these defects probably arise from progressive deterioration and swelling of a near-mature endolymphatic compartment after the development of an anatomically normal inner ear, as opposed to a simple arrest of development. It is also interesting to note that this widespread endolymphatic swelling is reminiscent of the endolymphatic hydrops seen in Ménière’s disease, an acquired human disorder associated with both auditory and vestibular dysfunction (43,44). Interestingly, animal models of Ménière’s disease can be created by ablating the endolymphatic duct and sac (45), which are the major sites of Pds expression in the inner ear (16). Thus, Ménière’s disease and PS may have more in common than previously thought, with pathology of pendrin-producing cells perhaps contributing to the former.
Ultrastructural studies revealed additional insights about the potential role of pendrin in the inner ear. For example, the lack of pendrin’s anion-transport function may account for the absence of normal otoconia and occasional giant otoconia seen in Pds–/– mice. Giant otoconia are thought to be formed by the dissolution and reaggregation of smaller otoconia secondary to biochemical abnormalities of the endolymph (46). The lack of pendrin also appears to trigger the degeneration of normally developed sensory hair cells of the inner ear, starting at some point between P7 and P15. It is interesting to note that this occurs at the same time as the establishment of a mature endolymphatic fluid composition and the development of the endocochlear potential (which occur between P7 and P20 in mouse) (47,48). It is clear that some abnormality of fluid homeostasis is already present in Pds–/– mice by E15.5, as evidenced by the endolymphatic dilatation and otoconial abnormalities. However, by P7–P15, when other ion- and fluid-regulating pathways are becoming active, pendrin’s absence may lead to the development of an environment that is toxic to the sensory hair cells, resulting in their degeneration.
PS is strikingly different from other hereditary forms of early-onset deafness in that its phenotypic features can be variable (e.g. time of onset of deafness and presence of vestibular disease), with the deafness itself even occurring post-lingually in some individuals (1–5). Interestingly, our Pds-knockout mice also display variability in vestibular disease, while at the same time showing progressive degeneration of normally developed sensory hair cells associated with deafness. It has not escaped our attention that these features suggest a theoretical route for therapeutic intervention in PS, which might delay the onset or progression of deafness. Specifically, there might be a window of time postnatally when the detrimental effects of pendrin’s absence could be minimized by therapeutically altering the perturbed ionic environment of the inner ear. This notion deserves consideration in light of the above-mentioned similarities between PS and Ménière’s disease, with the latter being partially amenable to pharmacotherapy. Although additional data are certainly required to understand the ionic alterations caused by pendrin’s absence, the Pds–/– mouse model that we report here should provide a valuable experimental tool for investigating possible therapeutic options.
In summary, the development and characterization of a Pds–/– mouse have provided important clues about the aetiology of deafness in PS. The inner-ear abnormalities seen in these mice generally recapitulate the anatomic defects seen in individuals with PDS mutations, with our data now indicating that a degenerative process is central to the altered ultrastructure. Importantly, the Pds–/– mouse now provides an invaluable system for performing more detailed studies of pendrin function, such as establishing its precise anion transporter specificity, which should contribute to the rapidly growing insight about inner-ear structure and function.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Generation of a Pds-targeting construct
A targeting construct designed to disrupt the endogenous Pds gene was created by cloning PCR-generated genomic fragments into the vector pPNTloxP (49,50). Specifically, primers designed from the Pds cDNA sequence (GenBank AF167411) were used to perform exon-to-exon PCR with the Advantage cDNA polymerase mix (Clontech), resulting in the generation of two genomic fragments that flank exon 8 of Pds (see Fig. 1A and B for additional details; primer sequences available on request). Following restriction digestion, the two fragments were cloned into the appropriate sites within pPNTloxP.
Generation of a Pds-knockout allele and Pds–/– mice
The Pds-targeting construct was electroporated into TC1 cells (derived from the 129Sv/Ev mouse strain) (51). DNA was purified from 210 G418/FIAU-resistant colonies by standard protocols involving SDS/proteinase K treatment, phenol:chloroform extraction and ethanol precipitation. The resulting DNA was digested with BamHI and subjected to Southern blot analysis. A single G418/FIAU-resistant cell line was found to be the product of an authentic homologous recombination event (Fig. 1C). Cells from this line were injected into C57BL/6J blastocysts, with a total of 70 blastocysts implanted into six Swiss Webster pseudopregnant females. Of the 17 resulting pups, six were male chimeras. Four of these chimeras were propagated further (into both Black Swiss and 129Sv/Ev mouse strains), and germline transmission was seen in all four cases. All animals were treated in accordance with the NIH guidelines for the care and use of laboratory animals.
Genotyping
A single-tube multiplex PCR assay was designed to assay mice for the presence of the Pds+ and Pds– alleles. This assay utilized three primers: an exon 7-specific primer (5'-TGCCGATTTCATCGCTGG-3') which served as the forward primer for amplifying both alleles, an exon 8-specific primer (5'-GCATTGTAGTTCTTTTCCAAGTTGG-3') which uniquely amplified the Pds+ allele and a pPNTloxP-specific primer (5'-GGGTGCGGAGAAAGAGGTAATG-3') which uniquely amplified the Pds– allele. The PCR assay was performed with Advantage cDNA polymerase mix (Clontech) and equal concentrations (1 µM) of each primer. Amplification of the appropriate products from the Pds+ and Pds– alleles yielded 243 and 287 bp fragments, respectively (Fig. 1D). For analysis of mouse tails by PCR, genomic DNA was prepared by a standard desalting method (52).
RT–PCR and northern blot analysis
Kidney mRNA was purified from Pds+/+, Pds+/– and Pds–/– mice using the Micro Poly(A) Pure kit (Ambion). The purified mRNA was used to synthesize cDNA using the Advantage RT for PCR kit (Clontech). In addition, northern blots were prepared using 5 µg of each purified mRNA sample and reagents provided with the Northern Gly-Max kit (Ambion); the resulting blots were hybridized with a 782 bp Pds-specific PCR product (generated from mouse kidney cDNA using primers 5'-CCACGTTAGACACTGGAACC-3' and 5'-GGCAACCATCACAATCACAGC-3') in ExpressHyb solution (Clontech) according to the manufacturer’s instructions.
Rotorod testing
A total of 35 mice of 7–9 weeks of age (10 Pds+/+, 13 Pds+/– and 12 Pds–/–) derived from heterozygous matings were assessed for their ability to balance on an accelerating revolving rod (rotorod) of 2.5 cm diameter. For each test, a mouse was placed on the rod rotating at 4 r.p.m. The rotation speed was then increased from 4 to 40 r.p.m. over 1 min, and the time until the mouse fell off of the rod (i.e. latency to fall) was recorded. Each mouse was tested four times each day (separated by at least 15 min) for 9 consecutive days (always within the same 4 h time window). For each group of mice, the mean latency to fall was calculated for the tests performed on each day; standard errors were calculated from the daily means of each mouse.
Auditory brainstem response (ABR) testing
A computer-aided evoked potential system (Intelligent Hearing System) was used to test mice for ABR thresholds using a modification of the described procedures (53). The IHS Smart-EP version 10, modified for high-frequency capability and coupled to high-frequency transducers, was used to generate specific acoustic stimuli and to amplify, measure and display the evoked brainstem responses of anaesthetized mice (tribromoethanol; 5.3 mg/10 g body wt, intraperitoneal). Subdermal needle electrodes were inserted at the vertex (active), ventrolaterally to the right ear (reference) and the left ear (ground). Specific acoustic stimuli were delivered binaurally through plastic tubes channelled from the high-frequency transducers. Mice were tested with click stimuli as well as with 8, 16 and 32 kHz tone pips at varying intensity [from low to high (10–100 dB SPL)]. Acoustic stimuli were presented for 50 µs (click) and 2.5 ms (pure-tone) at a rate of 19.1/s. ABR thresholds were determined for each stimulus frequency by identifying the lowest intensity producing a recognizable ABR pattern (at least two consistent peaks above the baseline). Mice were kept on a heating pad in a sound-proof chamber during testing.
Inner-ear paint-injection studies and histology
The membranous labyrinths of embryonic inner ears from mice at various developmental stages were injected with a methyl salicylate solution containing latex paint as described by Morsli et al. (34). For postnatal inner ears, heads were hemisectioned before fixation and microinjection was performed into the medial side of the inner ear. Pds–/– mice were examined at each of the following developmental stages: E13.5 (n = 4), E15 (n = 3), E15.5 (n = 5), E16.5 (n = 7), E18.5 (n = 18) and P1 (n = 6). After paint-fill, selected specimens were processed for paraffin sectioning followed by haematoxylin and eosin staining.
Electron microscopy
Mouse inner ears were dissected in 1.5% glutaraldehyde/3 mM calcium chloride/0.1 M cacodylate buffer (pH 7.3) and then fixed for 2 h at room temperature. Microdissection was performed to expose the surface of the organ of Corti and vestibular system sensory epithelium. After several washes in PBS, samples were treated with 1% osmium tetroxide for 15 min, dehydrated in ethanol, critical point dried, gold sputter coated and examined in a field emission scanning electron microscope (S-4500; Hitachi).
Fluorescence confocal microscopy
Dissected organs of Corti and vestibular tissue were fixed in 4% paraformaldehyde for 2 h at room temperature and permeabilized in 0.5% Triton X-100 for 30 min. Tissues were stained with 2 µg/ml fluorescein-conjugated phalloidin (Sigma) in blocking solution (2% bovine serum albumin in PBS) for 15 min. After several washes in PBS, samples were mounted using the ProLong Antifade kit (Molecular Probes) and examined with a laser scanning confocal microscope (LSM510).
Serum biochemistry and thyroid histology
Terminal blood samples obtained from 4-month-old, anaesthetized mice were tested for thyroid-stimulating hormone, total T3, total T4, reverse T3, albumin, sodium, potassium, chloride, bicarbonate, calcium, phosphate, urea and creatinine using standard methods (Anilytics). Mouse thyroids (obtained from animals at 1–5 months of age) were examined macroscopically and then processed for paraffin sectioning by routine methods.
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ACKNOWLEDGEMENTS |
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We thank Drs Dave Bodine, Bob Nussbaum, Dan Tagle, Georgina Miller and Tracy Young for advice and assistance. We also thank Drs Jim Battey, Bill Pavan, Bob Nussbaum and Pam Schwartzberg for critical review of the manuscript.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +1 301 402 0201; Fax: +1 301 402 4735; Email: egreen@nhgri.nih.gov
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REFERENCES |
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