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Centre de Recherche en neurobiologie et neurophysiologie de Marseille (CRN2M) (F.C., A.S., R.R., M.H.Q., F.A., A.E., A.Ba., T.B.), Unité Mixte de Recherche 6231, Faculté de Médecine Nord, Centre National de la Recherche Scientifique, Université de la Méditerranée and Centre de Référence des déficits hypophysaires, Hôpital de la Timone, Assistance Publique Hôpitaux de Marseille, 13385 Marseille, France; Laboratoire de Biochimie-Biologie Moléculaire (A.S., A.E., A.Ba.), Hôpital Conception, 13005 Marseille, France; Service de Pédiatrie (A.Bu.), Centre Hospitalier Chambéry, 73000 Chambéry France; Université Paris-Descartes et Assistance Publique–Hôpitaux de Paris (R.B.), Hôpital Bicêtre, 94270 Le Kremlin Bicêtre, France; Service d’endocrinologie (N.K.), Centre Hospitalier Universitaire Hedi-Chaker, route El-Ain, 3029 Sfax, Tunisie; Service des Maladies Métaboliques et Endocriniennes (A.M.G.), Centre Hospitalier Universitaire de Nîmes, 30000 Nîmes France; Department of Paediatrics (M.E.K.), Ain Shams University, 11566 Cairo, Egypt; Department of Paediatrics (M.A.), Cairo University, 11566 Cairo, Egypt
Address all correspondence and requests for reprints to: Professor T. Brue, Department of Endocrinology, Hôpital de la Timone, 264 rue St Pierre, cedex 5, 13385 Marseille, France. E-mail: thierry.brue{at}mail.ap-hm.fr.
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Abstract |
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Subjects and Methods: A total of 136 patients with congenital hypopituitarism associated with malformations of brain structures, pituitary stalk, or posterior pituitary gland was screened for LHX4 mutations.
Results: Three novel allelic variants that cause predicted changes in the protein sequence of LHX4 (2.3%) were found (p.Thr99fs, p.Thr90Met, and p.Gly370Ser). On the basis of functional studies, p.Thr99fs mutation was responsible for the patients’ phenotype, whereas p.Thr90Met and p.Gly370Ser were likely polymorphisms. Patients bearing the heterozygous p.Thr99fs mutation had variable phenotypes: two brothers presented somato-lactotroph and thyrotroph deficiencies, with pituitary hypoplasia and poorly developed sella turcica; the youngest brother (propositus) also had corpus callosum hypoplasia and ectopic neurohypophysis; their father only had somatotroph deficiency and delayed puberty with pituitary hyperplasia. Functional studies showed that the mutation induced a complete loss of transcriptional activity on POU1F1 promoter and a lack of DNA binding. Cotransfection of p.Thr99fs mutant and wild-type LHX4 failed to evidence any dominant negative effect, suggesting a mechanism of haploinsufficiency. We also identified prolactin and GH promoters as potential target genes of LHX4 and found that the p.Thr99fs mutant was also unable to transactivate these promoters.
Conclusions: The present report describes three new exonic LHX4 allelic variants with at least one being responsible for congenital hypopituitarism. It also extends the phenotypical heterogeneity associated with LHX4 mutations, which includes variable anterior pituitary hormone deficits, as well as pituitary and extrapituitary abnormalities.
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Introduction |
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LHX4 is a LIM homeodomain transcription factor crucial for the genesis and development of Rathke’s pouch (5, 6, 7). In mice, homozygous lhx4 invalidation by homologous recombination induces an abnormal pituitary phenotype and early, death but heterozygous animals display no apparent phenotypical modification (8, 9). In humans, only four functionally defective mutations of LHX4 have previously been described. The first one consists of a germline intronic splice-site mutation responsible for a short stature syndrome, due to GH deficiency. Pituitary phenotype also included TSH and ACTH deficiencies, whereas gonadotroph axis evaluation was not available due to the young age of the patients. Pituitary magnetic resonance imaging (MRI) revealed hindbrain defects in combination with abnormalities of the sella turcica and of the central skull base (10). Functional studies showed an abolished cooperative interaction between LHX4 and another transcription factor, POU1F1, whose proximal promoter has a recognition site for LIM domain transcription factors (11). Recently, another group reported three new LHX4 mutations with variable pituitary phenotypes (including nonconstant GH, TSH, ACTH and LH and FSH deficiencies) and hypoplasic pituitary on MRI with nonconstant ectopic posterior lobe and the lack of other brain malformations. Two of the three mutants had impaired DNA binding, and the third had reduced activity on 
GSU, POU1F1, and TSHβ promoters (12).
A striking feature was that all of these four mutations were heterozygous and likely to act through a mechanism of haploinsufficiency (11).
Another group reported a heterozygous exonic missense LHX4 allelic variant in a young baby presenting with panhypopituitarism, Chiari syndrome, and ectopic neurohypophysis (13). However, no functional study was performed, and, thus, it is not sure that this allelic variant was responsible for the phenotype.
Within a multicenter study of genetic determinants of pituitary deficiencies (GENHYPOPIT Network), 136 patients (from 133 pedigrees) were screened for LHX4 mutations because of congenital hypopituitarism associated with malformations of the brain, pituitary stalk, or posterior pituitary gland. Our primary objective was to search for novel LHX4 mutations in this extended cohort, and our secondary objective was to identify new potential target genes. In this paper we present three new allelic variants of LHX4 that cause predicted changes in protein sequence: Thr99fs, Thr90Met, and Gly370Ser. Functional studies showed that only the frameshift mutation was defective in its transcriptional activity on the POU1F1 promoter, probably due to the lack of DNA binding. We found a striking variability in phenotypical presentation in terms of associated pituitary hormone deficits and morphological abnormalities within the same pedigree. We also identified GH and prolactin (PRL) promoters as potential in vitro target genes of LHX4 and found that the p.Thr99fs mutation was also defective in its ability to transactivate both of these promoters. Thus, the present study allowed us to extend the pattern of phenotypes associated with LHX4 mutations: pituitary hyperplasia and corpus callosum hypoplasia may be associated with variable patterns of anterior pituitary hormone deficits.
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Subjects and Methods |
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The GENHYPOPIT network was launched as a multicentric study in both national (France) and international pediatric and adult endocrinology centers (Argentina, Belgium, Egypt, Lebanon, Switzerland, Tunisia, and Turkey). Screening for LHX4 mutations was performed in 136 patients (from 133 pedigrees). A total of 39 of the patients of this cohort had been included in a previous report, and the LHX4 allelic variant that was included in the latter study was found in the family reported by Machinis et al. (10), referred to as "pedigree D" in the present paper. In this study, patients bearing congenital hypopituitarism associated with malformations of the brain, pituitary stalk, or pituitary posterior gland were selected for LHX4 mutation screening on the basis of the first report by Machinis et al. (10), and murine models (14). Seven of the unrelated patients had other members of the family presenting with CPHD phenotype (familial cases). All patients or parents of minors gave their written informed consent to participate in this study, which was approved by our institutional ethics committee.
Hormonal studies and intracranial imaging were performed in all patients in each referring medical center, as previously described (15). On MRI, malformations were systematically sought and recorded in all patients. Patients with a known postnatal cause of acquired hypopituitarism were excluded.
We also report the phenotypical evolution of the two patients presenting with the first published mutation of LHX4 (intron 4 c.607–1G>C). Due to their young age at diagnosis, gonadotroph axis evaluation was not available at the initial report. After their family moved, they were referred to our center for further follow-up, with pituitary hormone evaluation, including gonadotroph axis, and cerebral MRI. These patients are referred to in the text as "Pedigree D."
Screening for LHX4 mutations
LHX4 sequence was amplified from peripheral blood DNA. Genomic analysis of LHX4 was performed by direct sequencing. The six coding exons of LHX4 were amplified from genomic DNA using exon-flanking primers (published as supplemental data on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org). The same primers were used for sequencing, using CEQ 8000 sequencer (Beckman Coulter, Fullerton, CA). According to the previously described genotyping algorithm, other candidate genes [PROP1, POU1F1, HESX1, and LHX3 (15)] had previously been sequenced, and no alteration had been found in coding regions. In parallel, 37 normal subjects were screened as controls for LHX4 mutations and polymorphisms.
Plasmid constructs and genomic analyses
LHX4 in plasmid pCMV-XL5 was purchased from Origene Technologies, Inc. (Rockville, MD). In vitro site-directed mutagenesis was achieved using the Quick-Change kit (Stratagene cloning system; Stratagene, La Jolla, CA) according to the manufacturer’s instructions. In brief, Pfu DNA polymerase was used to react 50-ng template DNA with the mutant sense primer and mutant antisense primer. This reaction involved 30-sec denaturation at 94 C and 12 cycles consisting of 30-sec denaturation at 94 C, 1-min annealing at 55 C, and 2-min extension at 72 C. After DNA purification and amplification (QIAGEN maxi kit; QIAGEN, Chatsworth, CA), the correct sequence was confirmed by DNA sequencing. Mutagenesis primers used for p.Thr99fs, p.Thr90Met, and p.Gly370Ser allelic variants are given in the supplemental data.
EMSA
Gel mobility shift assays were performed to assess the DNA binding properties of the LHX4 mutants. Wild-type and mutant LHX4 were transcribed and translated using the trinitrotoluene-coupled reticulocyte lysate system with T7 polymerase (Promega Corp., Madison, WI). Annealed synthetic oligonucleotides with GSU promoter LIM consensus sequence, as previously described (12, 16), were labeled with [32P]deoxy-CTP. Immunodepletion (supershift assay) was performed with 0.5 µg/well rabbit anti-LHX4 affinity purified polyclonal antibody (CHEMICON International, Inc. Temecula, CA). The protein-DNA complexes were analyzed by electrophoresis through a 8% polyacrylamide gel containing 2.5% glycerol in a 0.5x Tris borate buffer at 4 C.
Protein translation study
Wild-type and mutant LHX4 were transcribed and translated using the same reticulocyte lysate system but with nonradioactive amino acid mixture minus methionine and [35S]methionine. The protein expression was analyzed by electrophoresis on a 12% sodium dodecyl sulfate polyacrylamide gel and then detected by autoradiography.
Cell culture and cotransfection
Reporter constructs containing different gene-regulatory regions with putative LIM factor binding sites were fused to a firefly luciferase gene. These constructs included the proximal promoter regions of the human PRL gene (PRL-250) (a gift of J. A. Martial, Liege, Belgium) (17), or the proximal promoter of the human GH gene (Pa3 Ghp-Luc) (a gift of N. L. Eberhardt, Rochester, MN) (18), or the positive autoregulatory site of the human POU1F1 promoter gene (a gift of M. Delhase, San Diego, CA) (19). All nucleotide numbering was relative to the transcription start site.
Human heterologous HeLa cells were cultured and transfected as follows: 0.3–0.6 ng reporter constructs (PRL-250, GH, or POU1F1 promoter) and 0.6 ng effector construct (pCMV-XL5 empty vector or wild-type or mutant LHX4) per well were cotransfected using the liposome technique (Polyfect transfection reagent; QIAGEN, Hilden, Germany). Total DNA was kept constant with pCMV-XL5 empty vector, which also acted as a control. Transfection efficiency was determined using 0.01 ng pCMV-Renilla, and luciferase firefly values were normalized to it. Firefly and Renilla luciferase activity was measured 48 h after transfection. All assay points were performed in triplicate. Results are expressed in relative units (fold increase vs. empty vector).
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Results |
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Endocrine and neuroradiological phenotypes LHX4 screening was performed in 136 patients, from 133 pedigrees. Seven of the 133 unrelated patients screened had a history of familial CPHD (5.3%). Briefly, all but one patient presented with GH deficiency, 65% had TSH deficiency, and 48% had ACTH deficiency. Of the 74 patients that could be evaluated in terms of pubertal age, 60 presented with FSH/LH deficiencies (81%). Of the patients, 76% had at least three pituitary deficiencies. The most frequent encephalic MRI abnormalities were pituitary hypoplasia in 70% of cases, abnormal pituitary stalk in 63% of cases (nine patients with a very thin pituitary stalk, and 65 with a pituitary stalk interruption), and ectopic neurohypophysis in 31% of cases. Associated cerebral abnormalities were less frequent, with 8% of patients presenting with Chiari malformation, and 5% with corpus callosum hypoplasia or median line abnormalities. Only 3% of screened patients had septooptic dysplasia. One patient presented cerebellar dysplasia; another had craniostenosis.
Genomic analyses of the 136 patients
Three of our unrelated patients had unpublished LHX4 allelic variants (2.3%): p.Thr99fs, (pedigree A), p.Thr90Met (pedigree B), and p.Gly370Ser (pedigree C). LHX4 polymorphisms were found in 54% of our patients; 49.5% of them were carrying the previously described p.Asn328Ser polymorphism (Table 1
). None of the subjects from the control population bore any of the three unpublished LHX4 allelic variants. The frequency of each of the other polymorphisms was similar in our control population and in previously published reports.
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Pedigree A: p.Thr99fs LHX4 variant (Fig. 1, Table 2)
Phenotype
The propositus (patient III1) was referred to a pediatrician for short stature and micropenis at the age of 9 months. He was then –4 SD for height and weight with a normal head circumference. Hormonal data showed somatotroph and thyrotroph deficiencies. MRI showed poorly developed sella turcica, marked pituitary hypoplasia, thin pituitary stalk, lack of visible neurohypophysis, and corpus callosum hypoplasia (Fig. 1B, images A1 and A2). His brother (patient III2) was 4 yr old, with a short stature (–2 SD). Hormonal data showed somatotroph and thyrotroph deficiencies. MRI showed poorly developed sella turcica, pituitary hypoplasia, and normal pituitary stalk and neurohypophysis (Fig. 1B, images B1 and B2). As depicted in Fig. 2, A and B, both affected brothers had a poorly developed shallow, sella turcica without normal concavity of the sellar floor.
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, images C1 and C2). The mother of the propositus had no hormonal abnormalities. No other members of the family were available for assessment.
Genotype
Genetic analyses showed that the propositus, his brother, and his father carried the same heterozygous p.Thr99fs LHX4 allelic variant, with cytosine insertion in the third exon of LHX4 (c.293_294 InsC). At protein level, this predicts a frameshift (p.Thr99 frameshift) in the second LIM region with a stop codon occurring 53 amino acids after codon 99 (p.Thr99AsnfsX53). The mother did not carry the mutation. No other family member was available for genetic studies (Fig. 1).
Pedigree B: p.Thr90Met LHX4 variant
Phenotype The propositus was referred to an endocrinologist at the age of 50 yr. This man had been diagnosed at the age of 10 yr with somatotroph and corticotroph deficiencies. Delayed puberty also confirmed at the age of 16 yr the diagnosis of gonadotroph deficiency. He received hydrocortisone, testosterone, and GH replacement therapy. At the age of 50 yr, pituitary MRI disclosed ectopic neurohypophysis (at the higher part of the stalk), a thin pituitary stalk, and an empty sella syndrome.
His father did not have any baseline hormonal abnormalities (data not shown). No other members of the family were available for assessment.
Genotype Genetic analyses revealed that the propositus was bearing the allelic variant p.Thr90Met in a heterozygous state. Only his father could be tested by sequence analyses; he was not bearing this allelic variant. The propositus and his clinically unaffected father both bore the c.778 + 14 G>T polymorphism in a heterozygous state.
Pedigree C: p.Gly370Ser LHX4 variant
Phenotype The propositus was referred to a pediatrician at the age of 18 yr. She had somatotroph, corticotroph, and thyrotroph deficiencies. Pituitary MRI displayed pituitary hypoplasia with pituitary stalk interruption, but no neurohypophysis abnormalities. Her mother did not have any hormonal abnormalities. No other members of the family were evaluated.
Genotype Genetic analyses showed that the propositus was bearing the allelic variant p.Gly370Ser in a heterozygous state. Only her mother was available for sequencing analyses; she was not bearing this allelic variant. The propositus and her clinically unaffected mother were also bearing the previously described polymorphism p.Asn328Ser in a heterozygous state.
Phenotypical update of a previously described family (Pedigree D) carrying an intronic LHX4 mutation (intron 4 c.607–1 G>C)
Machinis et al. (10) previously described the same siblings (a brother and sister) carrying an intronic splice site allelic variant (G to C substitution in the intron preceding exon 5), responsible for somatotroph, lactotroph, and corticotroph deficiencies. At the first publication, both children were too young for their gonadal axis to be evaluated, and an update was necessary regarding the outcome of the endocrine phenotype. The brother was now aged 18 yr, and he presented with complete gonadotroph deficiency. Under appropriate GH and testosterone replacement therapy, he had reached normal height. Cerebral MRI performed at the age of 17 yr confirmed previous findings with a small sella turcica and a hypoplastic anterior hypophysis associated with ectopic posterior hypophysis. The sister was now aged 15 yr. She began spontaneous puberty at the age of 14 yr and still receives somatotroph, corticotroph, and thyrotroph substitutive therapies. She was evaluated at Tanner stage IV and had not yet had menarche. Pituitary MRI was unchanged (Table 4).
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)As expected, a truncated protein was observed with the pThr99fs LHX4 mutant. In contrast, expression of pThr90Met and pGly370Ser was detected with the same molecular weight as wild-type LHX4.
Gel shift mobility assay (Fig. 2C)
DNA binding of the LHX4 wild-type and the three LHX4 mutants was tested on the GSU promoter LIM factor response element. Wild-type LHX4 had a strong detectable DNA binding that was displaced by anti-LHX4 antibody (supershift). No detectable DNA binding was observed with the pThr99fs mutant under the chosen experimental conditions, whereas pGly370Ser and had an equivalent DNA binding as wild-type LHX4. Interestingly, pThr90Met seemed to have a stronger DNA binding than wild-type LHX4.
Functional studies
As expected (11), cotransfection of wild-type LHX4 with POU1F1 promoter resulted in a strong stimulation of the luciferase reporter gene relative to the empty vector. No activation was observed with the p.Thr99fs mutant. Cotransfection of mutant p.Thr99fs and equivalent amounts of wild-type LHX4 did not modify the effect of the latter on POU1F1 promoter, excluding dominant negative effect.
In contrast, cotransfection of p.Thr90Met or p.Gly370Ser LHX4 allelic variants with the POU1F1 promoter resulted in equal luciferase activity stimulation relative to wild-type LHX4. Equimolar cotransfection of either p.Thr90Met or p.Gly370Ser LHX4 plasmids and wild-type LHX4 plasmids showed similar results to double dose of individual plasmids on POU1F1 promoter, excluding dominant negative effect of these allelic variants. These functional results showed that despite amino acid change, p.Thr90Met and p.Gly370Ser were probably nonfunctional polymorphisms (Fig. 3A).
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Based on the phenotypes of patients presenting mutations of LIM homeodomain transcription factors (namely in terms of somato-lactotroph deficiencies) (10, 20, 21), we decided to evaluate the effects of wild-type LHX4 on GH and PRL promoters. Cotransfection of wild-type LHX4 with both promoters resulted in a strong stimulation of the luciferase reporter gene (Fig. 3, B and C). This stimulatory effect was observed in a dose-dependent manner (data not shown).
To evaluate the functional significance of our three new LHX4 allelic variants on PRL and GH promoters, we cotransfected mutant LHX4 allelic variants with each of the promoters. No activation was found with the p.Thr99fs mutant, confirming the deleterious effect of this frameshift mutation. As shown for the POU1F1 promoter, cotransfection of mutant p.Thr99fs and equivalent amounts of wild-type LHX4 did not modify the stimulatory effect of the latter on PRL or GH promoters. In contrast, results obtained after cotransfection with p.Thr90Met or p.Gly370Ser were identical to wild-type LHX4, confirming that these allelic variants were probably polymorphisms (Fig. 3, B and C).
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Discussion |
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Clinical and MRI phenotypes of patients bearing mutations of LHX4 can be highly variable both within and between families as shown in Tables 3 and 4. For instance, endocrine testing and cerebral MRI revealed a wide variability in the phenotypes of the patients carrying the novel p.Thr99fs mutation, suggesting a variable phenotype of this mutation. Despite identical genotype, the father of the propositus presented few phenotypical signs compared with his children; he only presented delayed puberty, with a lack of thyrotroph deficiency, normal pituitary stalk, and sella turcica, and had reached normal final height. This could be attributed to the delayed appearance of somatotroph deficiency or to obesity. Because sequencing of PROP1, POU1F1, HESX1, and LHX3 in the affected members of this family were all negative, other genes might interfere with pituitary development in this family. Variability in the endocrine phenotypes was also present in patients bearing the first previously published intronic mutation of LHX4 (10) because we found only one of the probands to have gonadotroph deficiency at pubertal age. To summarize, high phenotypical variability was observed between pedigrees A and D in terms of endocrine profiles (inconstant corticotroph, thyrotroph and gonadotroph deficiencies), pituitary morphology (hypoplastic or hyperplastic), location of pituitary posterior lobe (normal or ectopic), pituitary stalk (thin or normal), or cerebral malformations (Chiari syndrome in two patients, corpus callosum hypoplasia in one patient, lack of malformation in two patients). Patients bearing the three recently published LHX4 mutations also presented extremely variable pituitary intrafamily or interfamily phenotypes (12). The high variability of endocrine phenotype could thus be accounted for by different degrees of expressivity, or by the implication of other epigenetic and/or environmental factors (23). The present study also allowed us to define better the MRI profile of patients bearing LHX4 mutations as shown in Table 4. First, one important phenotypical feature that was present in all four young patients with LHX4 mutations is poorly developed sella turcica. This finding suggests the possible interaction of LHX4 with other transcription factors involved in the development of sella turcica. Moreover, the fact that all four patients bearing LHX4 mutation (intron 4 c.607–1 G>C or p.Thr99fs) presented with poorly developed sella turcica makes it an important point in the patient selection method for LHX4 screening. It is noteworthy that this is not a constant feature because none of the recently described patients with novel LHX4 mutations had poorly developed sella turcica (12). Moreover, it is difficult to ascertain whether pituitary hypoplasia was a direct consequence of defective LHX4 function or may be secondarily associated with a poorly developed sella turcica. Second, pituitary hypoplasia was not always present, and a slightly hyperplastic gland was even observed in one case; in contrast to previously published data on PROP1, the older patient had the more hyperplastic pituitary. Pituitary hypoplasia was not unexpected because LHX4 is necessary for the survival of antehypophysis precursor cells (9). In contrast, the father of the propositus (patient III1) is the first patient described with LHX4 mutation and hyperplastic pituitary on MRI. Follow-up of the patients presenting the first-published mutation of LHX4 did not reveal any pituitary volume increase between the age of 5 and 18 yr. Pituitary hyperplasia has been described at an initial stage in association with PROP1 mutations (24, 25, 26, 27) as well as in cases of LHX3 mutations (21, 28).
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A secondary objective of this study was the identification of some potential new target genes of LHX4 that might account for the hormonal phenotype of LHX4 mutations. Previous studies reported LHX4 activation of pituitary target genes such as -glycoprotein, FSH β and TSH β (12, 30, 31, 32). We report a moderate stimulatory effect of wild-type LHX4 on GH promoter and a strong stimulatory effect on PRL promoter that could be explained by the presence of LIM domain consensus sequences on both promoters. However, no direct binding experiment was performed on these promoters. The high frequency of somatotroph deficiency in patients presenting with LHX4 mutations could be explained by the lack of stimulatory effects of mutant LHX4 (intron 4 c.607–1 G>C or p.Thr99fs) relative to wild-type LHX4 on GH promoter and indirectly on POU1F1 promoter. Further studies particularly on the DNA binding properties of LHX4 on these LIM homeodomain transcription factors consensus sequences, and identification of additional LHX4 target genes will allow us to understand better the physiological relevance of these findings in humans. The patients’ phenotypes could at least partly be accounted for by interactions of LHX4 with these new target genes.
To conclude, pathogenic LHX4 mutations are rare, with a prevalence of less than 1% in a cohort of 136 patients with CPHD and various pituitary or extrapituitary abnormalities. We identified a novel mutation, p.Thr99fs, responsible for variable anterior pituitary hormone deficiencies and MRI abnormalities. The high variability of the phenotypes of the patients within this new pedigree extends the pattern of phenotypes associated with LHX4 mutations, which includes not only multiple pituitary hormone deficiencies associated with pituitary hypoplasia, ectopic neurohypophysis, and Chiari syndrome, but also hyperplastic pituitary, poorly developed sella turcica, and inconstant brain malformations. This study provides additional evidence that the dominance of LHX4 mutations would be due to haploinsufficiency rather than a dominant negative effect of the altered proteins over normal LHX4.
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Acknowledgments |
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Footnotes |
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First Published Online April 29, 2008
1 * F.C. and A.S. contributed equally to this work. 
Abbreviations: CPHD, Combined pituitary hormone deficiency; MRI, magnetic resonance imaging; PRL, prolactin.
Received October 26, 2007.
Accepted April 21, 2008.
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