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Adele Schneider - One of the best experts on this subject based on the ideXlab platform.
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Novel PXDN biallelic variants in patients with Microphthalmia and anterior segment dysgenesis
Journal of Human Genetics, 2020Co-Authors: Celia Zazo-seco, Julie Plaisancié, Pierre Bitoun, Marta Corton, Ana Arteche, Carmen Ayuso, Adele Schneider, Dimitra Zafeiropoulou, Christian Gilissen, Olivier RocheAbstract:Microphthalmia, anophthalmia, and anterior segment dysgenesis are severe ocular developmental defects. There is a wide genetic heterogeneity leading to these ocular malformations. By using whole genome, exome and targeted sequencing in patients with ocular developmental anomalies, six biallelic pathogenic variants (including five novel variants) were identified in the PXDN gene in four families with Microphthalmia and anterior segment dysgenesis. Only 11 different mutations (11 families) have been described in this gene to date. The phenotype of these patients is variable in severity, ranging from cataract and developmental glaucoma to complex Microphthalmia. Interestingly, two unrelated patients of our series presented with an ocular phenotype including aniridia and microspherophakia. However, despite various phenotypic presentations and types of mutations, no genotype-phenotype correlation could be made. Thus, this work improves our knowledge of the recessive phenotype associated with biallelic variants in this gene and highlights the importance of screening PXDN in patients with anterior segment dysgenesis with or without Microphthalmia.
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clinical report of Microphthalmia and optic nerve coloboma associated with a de novo microdeletion of chromosome 16p11 2
American Journal of Medical Genetics Part A, 2010Co-Authors: Tanya Bardakjian, Simon C M Kwok, Anne Slavotinek, Adele SchneiderAbstract:Anophthalmia and Microphthalmia are etiologically and clinically heterogeneous. We present a 13-year-old boy with Microphthalmia and multiple anomalies who was evaluated as part of our research into the etiology of Microphthalmia. His clinical features included left Microphthalmia, persistent hyperplastic primary vitreous and posterior coloboma, right posterior pole coloboma, pectus excavatum, mild hypotonia, mild delays in speech and motor development, and an anxiety disorder with social difficulties. Investigations with a chromosome microarray revealed a de novo deletion of chromosome 16p11.2 of approximately 882 kb in size. Deletions of this region of chromosome 16p11.2 are a newly delineated microdeletion syndrome, but this is the first report of Microphthalmia and coloboma associated with monosomy for 16p11.2, and emphasizes the clinical variability that can be present with this deletion. This report contributes to the growing knowledge regarding this microdeletion and suggests that rare copy number changes may be a cause of Microphthalmia and other eye anomalies. © 2010 Wiley-Liss, Inc.
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a male with unilateral Microphthalmia reveals a role for tmx3 in eye development
PLOS ONE, 2010Co-Authors: Ryan Chao, Tanya Bardakjian, Linda M Nevin, Pooja Agarwal, Jan Riemer, Xiaoyang Bai, Allen Delaney, Matthew Akana, Nelson Jimenezlopez, Adele SchneiderAbstract:Anophthalmia and Microphthalmia are important birth defects, but their pathogenesis remains incompletely understood. We studied a patient with severe unilateral Microphthalmia who had a 2.7 Mb deletion at chromosome 18q22.1 that was inherited from his mother. In-situ hybridization showed that one of the deleted genes, TMX3, was expressed in the retinal neuroepithelium and lens epithelium in the developing murine eye. We re-sequenced TMX3 in 162 patients with anophthalmia or Microphthalmia, and found two missense substitutions in unrelated patients: c.116G>A, predicting p.Arg39Gln, in a male with unilateral Microphthalmia and retinal coloboma, and c.322G>A, predicting p.Asp108Asn, in a female with unilateral Microphthalmia and severe micrognathia. We used two antisense morpholinos targeted against the zebrafish TMX3 orthologue, zgc:110025, to examine the effects of reduced gene expression in eye development. We noted that the morphant larvae resulting from both morpholinos had significantly smaller eye sizes and reduced labeling with islet-1 antibody directed against retinal ganglion cells at 2 days post fertilization. Co-injection of human wild type TMX3 mRNA rescued the small eye phenotype obtained with both morpholinos, whereas co-injection of human TMX3(p.Arg39Gln) mutant mRNA, analogous to the mutation in the patient with Microphthalmia and coloboma, did not rescue the small eye phenotype. Our results show that haploinsufficiency for TMX3 results in a small eye phenotype and represents a novel genetic cause of Microphthalmia and coloboma. Future experiments to determine if other thioredoxins are important in eye morphogenesis and to clarify the mechanism of function of TMX3 in eye development are warranted.
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FOXE3 plays a significant role in autosomal recessive Microphthalmia.
American journal of medical genetics. Part A, 2010Co-Authors: Linda M Reis, Adele Schneider, Tanya Bardakjian, Rebecca C Tyler, Joan M Stoler, Serge B Melancon, Elena V SeminaAbstract:FOXE3 forkhead transcription factor is essential to lens development in vertebrates. The eyes of Foxe3/foxe3-deficient mice and zebrafish fail to develop normally. In humans, autosomal dominant and recessive mutations in FOXE3 have been associated with variable phenotypes including anterior segment anomalies, cataract, and Microphthalmia. We undertook sequencing of FOXE3 in 116 probands with a spectrum of ocular defects ranging from anterior segment dysgenesis and cataract to anophthalmia/Microphthalmia. Recessive mutations in FOXE3 were found in four of 26 probands affected with bilateral Microphthalmia (15% of all bilateral Microphthalmia and 100% of consanguineous families with this phenotype). FOXE3-positive Microphthalmia was accompanied by aphakia and/or corneal defects; no other associated systemic anomalies were observed in FOXE3-positive families. The previously reported c.720C > A (p.C240X) nonsense mutation was identified in two additional families in our sample and therefore appears to be recurrent, now reported in three independent Microphthalmia families of varied ethnic backgrounds. Several missense variants were identified at varying frequencies in patient and control groups with some apparently being race-specific, which underscores the importance of utilizing race/ethnicity-matched control populations in evaluating the relevance of genetic screening results. In conclusion, FOXE3 mutations represent an important cause of nonsyndromic autosomal recessive bilateral Microphthalmia.
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Association of a de novo 16q copy number variant with a phenotype that overlaps with Lenz Microphthalmia and Townes-Brocks syndromes.
BMC medical genetics, 2009Co-Authors: Tanya Bardakjian, Adele Schneider, Jennifer J. Johnston, Leslie G. BieseckerAbstract:Background Anophthalmia and Microphthalmia are etiologically and clinically heterogeneous. Lenz Microphthalmia is a syndromic form that is typically inherited in an X-linked pattern, though the causative gene mutation is unknown. Townes-Brocks syndrome manifests thumb anomalies, imperforate anus, and ear anomalies. We present a 13-year-old boy with a syndromic Microphthalmia phenotype and a clinical diagnosis of Lenz Microphthalmia syndrome.
Ron Rabinowitz - One of the best experts on this subject based on the ideXlab platform.
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new rab3gap1 mutations in patients with warburg micro syndrome from different ethnic backgrounds and a possible founder effect in the danish
European Journal of Human Genetics, 2010Co-Authors: Deborah J Morrisrosendahl, Reeval Segel, Christoph Conrad, Bart Loeys, Laura Müller, Christine Zeschnigk, Christina Botti, Peter A Born, Susan Sklower Brooks, Ron RabinowitzAbstract:Warburg Micro Syndrome is a rare, autosomal recessive syndrome characterized by microcephaly, Microphthalmia, microcornia, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism. We have found five new mutations in the RAB3GAP1 gene in seven patients with suspected Micro Syndrome from families with Turkish, Palestinian, Danish, and Guatemalan backgrounds. A thorough clinical investigation of the patients has allowed the delineation of symptoms that are consistently present in the patients and may aid the differential diagnosis of Micro Syndrome for patients in the future. All patients had postnatal microcephaly, micropthalmia, microcornia, bilateral congenital cataracts, short palpebral fissures, optic atrophy, severe mental retardation, and congenital hypotonia with subsequent spasticity. Only one patient had microcephaly at birth, highlighting the fact that congenital microcephaly is not a consistent feature of Micro syndrome. Analysis of the brain magnetic resonance imagings (MRIs) revealed a consistent pattern of polymicrogyria in the frontal and parietal lobes, wide sylvian fissures, a thin hypoplastic corpus callosum, and increased subdural spaces. All patients were homozygous for the mutations detected and all mutations were predicted to result in a truncated RAB3GAP1 protein. The analysis of nine polymorphic markers flanking the RAB3GAP1 gene showed that the mutation c.1410C>A (p.Tyr470X), for which a Danish patient was homozygous, occurred on a haplotype that is shared by the unrelated heterozygous parents of the patient. This suggests a possible founder effect for this mutation in the Danish population.
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New mutations in the RAB3GAP1 gene in patients with Warburg MICRO Syndrome and a possible founder effect in the Danish population
European Journal of Human Genetics, 2010Co-Authors: Deborah J Morris-rosendahl, Reeval Segel, A. Peter Born, Christoph Conrad, Bart Loeys, Susan Sklower Brooks, Laura Müller, Christine Zeschnigk, Christina Botti, Ron RabinowitzAbstract:Warburg MICRO Syndrome is a rare, autosomal recessive syndrome characterized by microcephaly, Microphthalmia, microcornia, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism. We have found five new mutations in the RAB3GAP1 gene in seven patients with suspected MICRO Syndrome, from families with Turkish, Palestinian, Danish and Guatemalan backgrounds. A thorough clinical investigation of the patients has allowed the delineation of symptoms which are consistently present in the patients and may aid the differential diagnosis of MICRO Syndrome for patients in the future. All patients had postnatal microcephaly, micropthalmia, microcornia, bilateral congenital cataracts, short palpebral fissures, optic atrophy, severe mental retardation, and congenital hypotonia with subsequent spasticity. Only one patient had microcephaly at birth, highlighting the fact that congenital microcephaly is not a consistent feature of MICRO syndrome. Analysis of the brain MRIs revealed a consistent pattern of polymicrogyria in the frontal and parietal lobes, wide sylvian fissures, a thin hypoplastic corpus callosum and increased subdural spaces. All patients were homozygous for the mutations detected and all mutations were predicted to result in a truncated RAB3GAP1 protein. The analysis of nine polymorphic markers flanking the RAB3GAP1 gene showed that the mutation c.1410C>A (p.Tyr470X), for which a Danish patient was homozygous, occurred on a haplotype that is shared by the unrelated heterozygous parents of the patient. This suggests a possible founder effect for this mutation in the Danish population.
Philip J. Lupo - One of the best experts on this subject based on the ideXlab platform.
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epidemiology of anophthalmia and Microphthalmia prevalence and patterns in texas 1999 2009
American Journal of Medical Genetics Part A, 2018Co-Authors: Tiffany M. Chambers, A. J. Agopian, Richard A. Lewis, Peter H. Langlois, Heather E. Danysh, Kari A. Weber, Gary M. Shaw, Laura E. Mitchell, Philip J. LupoAbstract:Anophthalmia and Microphthalmia are a set of rare, yet severe, birth defects considered to be part of a spectrum of developmental ocular malformations ranging from smaller than average to completely absent eyes. Despite their clinical significance, little is known about the etiologies of these conditions. The goal of this study was to expand our understanding of the epidemiology of anophthalmia and Microphthalmia. Data for this population-based assessment were obtained from the Texas Birth Defects Registry (TBDR) and Center for Health Statistics for the period 1999-2009. Descriptive analyses and estimates of birth prevalence and prevalence ratios (PR) were determined for this defect. There were 1,262 definite anophthalmia and Microphthalmia patients identified in the TBDR, with an overall combined prevalence of 3.0 per 10,000 live births. More than half (55.7%) of the patients had at least one chromosome abnormality or syndrome. In addition, 92.4% of nonsyndromic patients (i.e., have no recorded chromosome abnormalities or syndromes) had at least one additional birth defect. After adjustment for multiple factors, the prevalence of nonsyndromic anophthalmia and Microphthalmia was higher among mothers who had ≥2 previous fetal deaths (PR = 1.43, 95% confidence interval [CI]: 1.03-1.97) and among mothers with any reported diabetes (PR = 2.08, 95% CI: 1.49-2.90). Our results confirm that children with anophthalmia and Microphthalmia frequently have genetic syndromes or are born with other major birth defects. Our findings add to the limited body of literature on anophthalmia and Microphthalmia as well as help define subgroups of women who are more likely to have children with this malformation.
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Epidemiology of anophthalmia and Microphthalmia: Prevalence and patterns in Texas, 1999–2009
American journal of medical genetics. Part A, 2018Co-Authors: Tiffany M. Chambers, A. J. Agopian, Richard A. Lewis, Peter H. Langlois, Heather E. Danysh, Kari A. Weber, Gary M. Shaw, Laura E. Mitchell, Philip J. LupoAbstract:Anophthalmia and Microphthalmia are a set of rare, yet severe, birth defects considered to be part of a spectrum of developmental ocular malformations ranging from smaller than average to completely absent eyes. Despite their clinical significance, little is known about the etiologies of these conditions. The goal of this study was to expand our understanding of the epidemiology of anophthalmia and Microphthalmia. Data for this population-based assessment were obtained from the Texas Birth Defects Registry (TBDR) and Center for Health Statistics for the period 1999-2009. Descriptive analyses and estimates of birth prevalence and prevalence ratios (PR) were determined for this defect. There were 1,262 definite anophthalmia and Microphthalmia patients identified in the TBDR, with an overall combined prevalence of 3.0 per 10,000 live births. More than half (55.7%) of the patients had at least one chromosome abnormality or syndrome. In addition, 92.4% of nonsyndromic patients (i.e., have no recorded chromosome abnormalities or syndromes) had at least one additional birth defect. After adjustment for multiple factors, the prevalence of nonsyndromic anophthalmia and Microphthalmia was higher among mothers who had ≥2 previous fetal deaths (PR = 1.43, 95% confidence interval [CI]: 1.03-1.97) and among mothers with any reported diabetes (PR = 2.08, 95% CI: 1.49-2.90). Our results confirm that children with anophthalmia and Microphthalmia frequently have genetic syndromes or are born with other major birth defects. Our findings add to the limited body of literature on anophthalmia and Microphthalmia as well as help define subgroups of women who are more likely to have children with this malformation.
Robert Ballotti - One of the best experts on this subject based on the ideXlab platform.
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Microphthalmia Associated Transcription Factor Is a Target of the Phosphatidylinositol-3-Kinase Pathway
Journal of Investigative Dermatology, 2003Co-Authors: Mehdi Khaled, Karine Bille, Lionel Larribere, Jean-paul Ortonne, Robert Ballotti, Corine BertolottoAbstract:In B16 melanoma cells, cyclic adenosine monophosphate inhibits the phosphatidylinositol-3-kinase and the phosphatidylinositol-3-kinase inhibitor, LY294002, stimulates melanogenesis. However, the molecular mechanisms, by which phosphatidylinositol-3-kinase inhibition increases melanogenesis remained to be identified. In this study, we show that LY294002 up-regulates the expression of the melanogenic enzymes, tyrosinase and Tyrp1, through a transcriptional mechanism that involves Microphthalmia associated transcription factor, a basic helix-loop-helix transcription factor, which plays a key role in melanocyte survival and differentiation. Further, we observe that LY294002 increases the intracellular content of Microphthalmia associated transcription factor, thereby demonstrating that Microphthalmia associated transcription factor is also a convergence point of the phosphatidylinositol-3-kinase signaling pathway. Finally, our results indicate that LY294002 controls Microphthalmia associated transcription factor at the transcriptional level through distal regulatory element that remain to be identified. Interestingly, we have recently reported that cAMP-elevating agents, through a phosphatidylinositol-3-kinase/AKT inhibition and a glycogen synthase kinase 3β activation, may stimulate Microphthalmia associated transcription factor binding to its target sequence, suggesting that inhibition of the phosphatidylinositol-3-kinase is implicated in the stimulation of melanogenesis at different levels. Thus, the results presented in this report strengthen the importance of the phosphatidylinositol-3-kinase pathway in the regulation of melanogenesis and emphasize the complexity of the cyclic adenosine monophosphate signaling that controls melanocyte differentiation and melanogenesis.
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tfe3 a transcription factor homologous to Microphthalmia is a potential transcriptional activator of tyrosinase and tyrpi genes
Molecular Endocrinology, 2000Co-Authors: Carole Verastegui, Karine Bille, Jean-paul Ortonne, Corine Bertolotto, Patricia Abbe, Robert BallottiAbstract:Microphthalmia gene encodes a basic helix-loop-helix-leucine zipper (bHLH-Zip) transcription factor involved in the development of the melanocyte lineage and plays a key role in the transcriptional regulation of the melanogenic enzymes, tyrosinase and TyrpI. Recently, we have shown that Microphthalmia mediates the melanogenic effects elicited byα MSH that up-regulates the expression of tyrosinase through the activation of the cAMP pathway. Therefore, Microphthalmia appears as a principal gene in melanocyte development and functioning. Among the transcription factors of the bHLH-Zip family, TFE3 and TFEB show a remarkably elevated homology with Microphthalmia. These observations prompted us to investigate the role of TFE3 and TFEB in the regulation of tyrosinase and TyrpI gene transcription. We show in this report that overexpression of TFE3 stimulates the tyrosinase and TyrpI promoter activities, while TFEB acts only on the TyrpI promoter. TFE3 and TFEB elicit their effects mainly through the binding to M...
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Microphthalmia gene product as a signal transducer in camp induced differentiation of melanocytes
Journal of Cell Biology, 1998Co-Authors: Corine Bertolotto, Karine Bille, Jean-paul Ortonne, Patricia Abbe, Timothy J Hemesath, David E Fisher, Robert BallottiAbstract:Melanocyte differentiation characterized by an increased melanogenesis, is stimulated by α-melanocyte–stimulating hormone through activation of the cAMP pathway. During this process, the expression of tyrosinase, the enzyme that controls melanin synthesis is upregulated. We previously showed that cAMP regulates transcription of the tyrosinase gene through a CATGTG motif that binds Microphthalmia a transcription factor involved in melanocyte survival. Further, Microphthalmia stimulates the transcriptional activity of the tyrosinase promoter and cAMP increases the binding of Microphthalmia to the CATGTG motif. These observations led us to hypothesize that Microphthalmia mediates the effect of cAMP on the expression of tyrosinase. The present study was designed to elucidate the mechanism by which cAMP regulates Microphthalmia function and to prove our former hypothesis, suggesting that Microphthalmia is a key component in cAMP-induced melanogenesis. First, we showed that cAMP upregulates the transcription of Microphthalmia gene through a classical cAMP response element that is functional only in melanocytes. Then, using a dominant-negative mutant of Microphthalmia, we demonstrated that Microphthalmia is required for the cAMP effect on tyrosinase promoter. These findings disclose the mechanism by which cAMP stimulates tyrosinase expression and melanogenesis and emphasize the critical role of Microphthalmia as signal transducer in cAMP-induced melanogenesis and pigment cell differentiation.
Corine Bertolotto - One of the best experts on this subject based on the ideXlab platform.
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Microphthalmia Associated Transcription Factor Is a Target of the Phosphatidylinositol-3-Kinase Pathway
Journal of Investigative Dermatology, 2003Co-Authors: Mehdi Khaled, Karine Bille, Lionel Larribere, Jean-paul Ortonne, Robert Ballotti, Corine BertolottoAbstract:In B16 melanoma cells, cyclic adenosine monophosphate inhibits the phosphatidylinositol-3-kinase and the phosphatidylinositol-3-kinase inhibitor, LY294002, stimulates melanogenesis. However, the molecular mechanisms, by which phosphatidylinositol-3-kinase inhibition increases melanogenesis remained to be identified. In this study, we show that LY294002 up-regulates the expression of the melanogenic enzymes, tyrosinase and Tyrp1, through a transcriptional mechanism that involves Microphthalmia associated transcription factor, a basic helix-loop-helix transcription factor, which plays a key role in melanocyte survival and differentiation. Further, we observe that LY294002 increases the intracellular content of Microphthalmia associated transcription factor, thereby demonstrating that Microphthalmia associated transcription factor is also a convergence point of the phosphatidylinositol-3-kinase signaling pathway. Finally, our results indicate that LY294002 controls Microphthalmia associated transcription factor at the transcriptional level through distal regulatory element that remain to be identified. Interestingly, we have recently reported that cAMP-elevating agents, through a phosphatidylinositol-3-kinase/AKT inhibition and a glycogen synthase kinase 3β activation, may stimulate Microphthalmia associated transcription factor binding to its target sequence, suggesting that inhibition of the phosphatidylinositol-3-kinase is implicated in the stimulation of melanogenesis at different levels. Thus, the results presented in this report strengthen the importance of the phosphatidylinositol-3-kinase pathway in the regulation of melanogenesis and emphasize the complexity of the cyclic adenosine monophosphate signaling that controls melanocyte differentiation and melanogenesis.
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tfe3 a transcription factor homologous to Microphthalmia is a potential transcriptional activator of tyrosinase and tyrpi genes
Molecular Endocrinology, 2000Co-Authors: Carole Verastegui, Karine Bille, Jean-paul Ortonne, Corine Bertolotto, Patricia Abbe, Robert BallottiAbstract:Microphthalmia gene encodes a basic helix-loop-helix-leucine zipper (bHLH-Zip) transcription factor involved in the development of the melanocyte lineage and plays a key role in the transcriptional regulation of the melanogenic enzymes, tyrosinase and TyrpI. Recently, we have shown that Microphthalmia mediates the melanogenic effects elicited byα MSH that up-regulates the expression of tyrosinase through the activation of the cAMP pathway. Therefore, Microphthalmia appears as a principal gene in melanocyte development and functioning. Among the transcription factors of the bHLH-Zip family, TFE3 and TFEB show a remarkably elevated homology with Microphthalmia. These observations prompted us to investigate the role of TFE3 and TFEB in the regulation of tyrosinase and TyrpI gene transcription. We show in this report that overexpression of TFE3 stimulates the tyrosinase and TyrpI promoter activities, while TFEB acts only on the TyrpI promoter. TFE3 and TFEB elicit their effects mainly through the binding to M...
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Microphthalmia gene product as a signal transducer in camp induced differentiation of melanocytes
Journal of Cell Biology, 1998Co-Authors: Corine Bertolotto, Karine Bille, Jean-paul Ortonne, Patricia Abbe, Timothy J Hemesath, David E Fisher, Robert BallottiAbstract:Melanocyte differentiation characterized by an increased melanogenesis, is stimulated by α-melanocyte–stimulating hormone through activation of the cAMP pathway. During this process, the expression of tyrosinase, the enzyme that controls melanin synthesis is upregulated. We previously showed that cAMP regulates transcription of the tyrosinase gene through a CATGTG motif that binds Microphthalmia a transcription factor involved in melanocyte survival. Further, Microphthalmia stimulates the transcriptional activity of the tyrosinase promoter and cAMP increases the binding of Microphthalmia to the CATGTG motif. These observations led us to hypothesize that Microphthalmia mediates the effect of cAMP on the expression of tyrosinase. The present study was designed to elucidate the mechanism by which cAMP regulates Microphthalmia function and to prove our former hypothesis, suggesting that Microphthalmia is a key component in cAMP-induced melanogenesis. First, we showed that cAMP upregulates the transcription of Microphthalmia gene through a classical cAMP response element that is functional only in melanocytes. Then, using a dominant-negative mutant of Microphthalmia, we demonstrated that Microphthalmia is required for the cAMP effect on tyrosinase promoter. These findings disclose the mechanism by which cAMP stimulates tyrosinase expression and melanogenesis and emphasize the critical role of Microphthalmia as signal transducer in cAMP-induced melanogenesis and pigment cell differentiation.