The Experts below are selected from a list of 1278 Experts worldwide ranked by ideXlab platform
Mark J Mccabe - One of the best experts on this subject based on the ideXlab platform.
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novel application of luciferase assay for the in vitro functional assessment of kal1 variants in three females with septo optic Dysplasia sod
Molecular and Cellular Endocrinology, 2015Co-Authors: Mark J Mccabe, Carles Gastonmassuet, Louise C Gregory, Kyriaki S Alatzoglou, Youli Hu, Jose W SaldanhaAbstract:KAL1 is implicated in 5% of Kallmann syndrome cases, a disorder which genotypically overlaps with Septo-Optic Dysplasia (SOD). To date, a reporter-based assay to assess the functional consequences of KAL1 mutations is lacking. We aimed to develop a luciferase assay for novel application to functional assessment of rare KAL1 mutations detected in a screen of 422 patients with SOD. Quantitative analysis was performed using L6-myoblasts stably expressing FGFR1, transfected with a luciferase-reporter vector containing elements of the FGF-responsive osteocalcin promoter. The two variants assayed [p.K185N, p.P291T], were detected in three females with SOD (presenting with optic nerve hypoplasia, midline and pituitary defects). Our novel assay revealed significant decreases in transcriptional activity [p.K185N: 21% (p < 0.01); p.P291T: 40% (p < 0.001)]. Our luciferase-reporter assay, developed for assessment of KAL1 mutations, determined that two variants in females with hypopituitarism/SOD are loss-of-function; demonstrating that this assay is suitable for quantitative assessment of mutations in this gene.
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genetic aspects of hypothalamic and pituitary gland development
Handbook of Clinical Neurology, 2014Co-Authors: Mark J Mccabe, Mehul T. DattaniAbstract:Hypothalamo-pituitary development during embryogenesis is a highly complex process involving the interaction of a network of spatiotemporally regulated signaling molecules and transcription factors. Mutations in any of the genes encoding these components can lead to congenital hypopituitarism, which is often associated with a wide spectrum of defects affecting craniofacial/midline development. In turn, these defects can be incompatible with life, or lead to disorders encompassing holoprosencephaly (HPE) and cleft palate, and Septo-Optic Dysplasia (SOD). In recent years, there has been increasing evidence of an overlapping genotype between this spectrum of disorders and Kallmann syndrome (KS), defined as the association of hypogonadotropic hypogonadism (HH) and anosmia. This is consistent with the known phenotypic overlap between these disorders and opens a new avenue of identifying novel genetic causes of the hypopituitarism spectrum. This chapter reviews the genetic and molecular events leading to the successful development of the hypothalamo-pituitary axis during embryogenesis, and focuses on genes in which variations/mutations occur, leading to congenital hypopituitarism and associated defects.
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structural pituitary abnormalities associated with charge syndrome
The Journal of Clinical Endocrinology and Metabolism, 2013Co-Authors: Louise C Gregory, Mark J Mccabe, Ef Gevers, Dj Josifova, Joanne Baker, Tessa Kasia, Kling Chong, Maria Caimari, Frederic Bilan, Mehul T. DattaniAbstract:Introduction: CHARGE syndrome is a multisystem disorder that, in addition to Kallmann syndrome/isolated hypogonadotrophic hypogonadism, has been associated with anterior pituitary hypoplasia (APH). However, structural abnormalities such as an ectopic posterior pituitary (EPP) have not yet been described in such patients. Objective: The aims of the study were: 1) to describe the association between CHARGE syndrome and a structurally abnormal pituitary gland; and 2) to investigate whether CHD7 variants, which are identified in 65% of CHARGE patients, are common in Septo-Optic Dysplasia /hypopituitarism. Methods: We describe 2 patients with features of CHARGE and EPP. CHD7 was sequenced in these and other patients with Septo-Optic Dysplasia/hypopituitarism. Results: EPP, APH, and GH, TSH, and probable LH/FSH deficiency were present in 1 patient, and EPP and APH with GH, TSH, LH/FSH, and ACTH deficiency were present in another patient, both of whom had features of CHARGE syndrome. Both had variations in CHD7 ...
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variations in prokr2 but not prok2 are associated with hypopituitarism and septo optic Dysplasia
The Journal of Clinical Endocrinology and Metabolism, 2013Co-Authors: Mark J Mccabe, Vaitsa Tziaferi, Carles Gastonmassuet, Louise C Gregory, Kyriaki S Alatzoglou, Oualid Sbai, Philippe Rondard, Kohhei Masumoto, Mamoru Nagano, Yasufumi ShigeyoshiAbstract:Context: Loss-of-function mutations in PROK2 and PROKR2 have been implicated in Kallmann syndrome (KS), characterized by hypogonadotropic hypogonadism and anosmia. Recent data suggest overlapping phenotypes/genotypes between KS and congenital hypopituitarism (CH), including Septo-Optic Dysplasia (SOD). Objective: We screened a cohort of patients with complex forms of CH (n = 422) for mutations in PROK2 and PROKR2. Results: We detected 5 PROKR2 variants in 11 patients with SOD/CH: novel p.G371R and previously reported p.A51T, p.R85L, p.L173R, and p.R268C—the latter 3 being known functionally deleterious variants. Surprisingly, 1 patient with SOD was heterozygous for the p.L173R variant, whereas his phenotypically unaffected mother was homozygous for the variant. We sought to clarify the role of PROKR2 in hypothalamopituitary development through analysis of Prokr2−/− mice. Interestingly, these revealed predominantly normal hypothalamopituitary development and terminal cell differentiation, with the exceptio...
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pituitary gland development an update
Endocrine development, 2012Co-Authors: Rodrigo E Bancalari, Mark J Mccabe, Louise C Gregory, Mehul T. DattaniAbstract:The embryonic development of the pituitary gland involves a complex and highly spatio-temporally regulated network of integrating signalling molecules and transcription factors. Genetic mutations in any of these factors can lead to congenital hypopituitarism in association with a wide spectrum of craniofacial/midline defects ranging from incompatibility with life to holoprosencephaly (HPE) and cleft palate and Septo-Optic Dysplasia (SOD). Increasing evidence supports a genotypic overlap with hypogonadotrophic hypogonadal disorders such as Kallmann syndrome, which is consistent with the known overlap in phenotypes between these disorders. This chapter reviews the cascade of events leading up to the successful development of the pituitary gland and to highlight key areas where genetic variations can occur thus leading to congenital hypopituitarism and associated defects.
Louise C Gregory - One of the best experts on this subject based on the ideXlab platform.
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activating mutations in braf disrupt the hypothalamo pituitary axis leading to hypopituitarism in mice and humans
Nature Communications, 2021Co-Authors: Angelica Gualtieri, Louise C Gregory, Nikolina Kyprianou, Maria Lillina Vignola, James G Nicholson, Rachael Tan, Shin Ichi Inoue, Valeria Scagliotti, Pedro Casado, James BlackburnAbstract:Germline mutations in BRAF and other components of the MAPK pathway are associated with the congenital syndromes collectively known as RASopathies. Here, we report the association of Septo-Optic Dysplasia (SOD) including hypopituitarism and Cardio-Facio-Cutaneous (CFC) syndrome in patients harbouring mutations in BRAF. Phosphoproteomic analyses demonstrate that these genetic variants are gain-of-function mutations leading to activation of the MAPK pathway. Activation of the MAPK pathway by conditional expression of the BrafV600E/+ allele, or the knock-in BrafQ241R/+ allele (corresponding to the most frequent human CFC-causing mutation, BRAF p.Q257R), leads to abnormal cell lineage determination and terminal differentiation of hormone-producing cells, causing hypopituitarism. Expression of the BrafV600E/+ allele in embryonic pituitary progenitors leads to an increased expression of cell cycle inhibitors, cell growth arrest and apoptosis, but not tumour formation. Our findings show a critical role of BRAF in hypothalamo-pituitary-axis development both in mouse and human and implicate mutations found in RASopathies as a cause of endocrine deficiencies in humans.
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novel application of luciferase assay for the in vitro functional assessment of kal1 variants in three females with septo optic Dysplasia sod
Molecular and Cellular Endocrinology, 2015Co-Authors: Mark J Mccabe, Carles Gastonmassuet, Louise C Gregory, Kyriaki S Alatzoglou, Youli Hu, Jose W SaldanhaAbstract:KAL1 is implicated in 5% of Kallmann syndrome cases, a disorder which genotypically overlaps with Septo-Optic Dysplasia (SOD). To date, a reporter-based assay to assess the functional consequences of KAL1 mutations is lacking. We aimed to develop a luciferase assay for novel application to functional assessment of rare KAL1 mutations detected in a screen of 422 patients with SOD. Quantitative analysis was performed using L6-myoblasts stably expressing FGFR1, transfected with a luciferase-reporter vector containing elements of the FGF-responsive osteocalcin promoter. The two variants assayed [p.K185N, p.P291T], were detected in three females with SOD (presenting with optic nerve hypoplasia, midline and pituitary defects). Our novel assay revealed significant decreases in transcriptional activity [p.K185N: 21% (p < 0.01); p.P291T: 40% (p < 0.001)]. Our luciferase-reporter assay, developed for assessment of KAL1 mutations, determined that two variants in females with hypopituitarism/SOD are loss-of-function; demonstrating that this assay is suitable for quantitative assessment of mutations in this gene.
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structural pituitary abnormalities associated with charge syndrome
The Journal of Clinical Endocrinology and Metabolism, 2013Co-Authors: Louise C Gregory, Mark J Mccabe, Ef Gevers, Dj Josifova, Joanne Baker, Tessa Kasia, Kling Chong, Maria Caimari, Frederic Bilan, Mehul T. DattaniAbstract:Introduction: CHARGE syndrome is a multisystem disorder that, in addition to Kallmann syndrome/isolated hypogonadotrophic hypogonadism, has been associated with anterior pituitary hypoplasia (APH). However, structural abnormalities such as an ectopic posterior pituitary (EPP) have not yet been described in such patients. Objective: The aims of the study were: 1) to describe the association between CHARGE syndrome and a structurally abnormal pituitary gland; and 2) to investigate whether CHD7 variants, which are identified in 65% of CHARGE patients, are common in Septo-Optic Dysplasia /hypopituitarism. Methods: We describe 2 patients with features of CHARGE and EPP. CHD7 was sequenced in these and other patients with Septo-Optic Dysplasia/hypopituitarism. Results: EPP, APH, and GH, TSH, and probable LH/FSH deficiency were present in 1 patient, and EPP and APH with GH, TSH, LH/FSH, and ACTH deficiency were present in another patient, both of whom had features of CHARGE syndrome. Both had variations in CHD7 ...
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variations in prokr2 but not prok2 are associated with hypopituitarism and septo optic Dysplasia
The Journal of Clinical Endocrinology and Metabolism, 2013Co-Authors: Mark J Mccabe, Vaitsa Tziaferi, Carles Gastonmassuet, Louise C Gregory, Kyriaki S Alatzoglou, Oualid Sbai, Philippe Rondard, Kohhei Masumoto, Mamoru Nagano, Yasufumi ShigeyoshiAbstract:Context: Loss-of-function mutations in PROK2 and PROKR2 have been implicated in Kallmann syndrome (KS), characterized by hypogonadotropic hypogonadism and anosmia. Recent data suggest overlapping phenotypes/genotypes between KS and congenital hypopituitarism (CH), including Septo-Optic Dysplasia (SOD). Objective: We screened a cohort of patients with complex forms of CH (n = 422) for mutations in PROK2 and PROKR2. Results: We detected 5 PROKR2 variants in 11 patients with SOD/CH: novel p.G371R and previously reported p.A51T, p.R85L, p.L173R, and p.R268C—the latter 3 being known functionally deleterious variants. Surprisingly, 1 patient with SOD was heterozygous for the p.L173R variant, whereas his phenotypically unaffected mother was homozygous for the variant. We sought to clarify the role of PROKR2 in hypothalamopituitary development through analysis of Prokr2−/− mice. Interestingly, these revealed predominantly normal hypothalamopituitary development and terminal cell differentiation, with the exceptio...
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pituitary gland development an update
Endocrine development, 2012Co-Authors: Rodrigo E Bancalari, Mark J Mccabe, Louise C Gregory, Mehul T. DattaniAbstract:The embryonic development of the pituitary gland involves a complex and highly spatio-temporally regulated network of integrating signalling molecules and transcription factors. Genetic mutations in any of these factors can lead to congenital hypopituitarism in association with a wide spectrum of craniofacial/midline defects ranging from incompatibility with life to holoprosencephaly (HPE) and cleft palate and Septo-Optic Dysplasia (SOD). Increasing evidence supports a genotypic overlap with hypogonadotrophic hypogonadal disorders such as Kallmann syndrome, which is consistent with the known overlap in phenotypes between these disorders. This chapter reviews the cascade of events leading up to the successful development of the pituitary gland and to highlight key areas where genetic variations can occur thus leading to congenital hypopituitarism and associated defects.
Mehul T. Dattani - One of the best experts on this subject based on the ideXlab platform.
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genetic aspects of hypothalamic and pituitary gland development
Handbook of Clinical Neurology, 2014Co-Authors: Mark J Mccabe, Mehul T. DattaniAbstract:Hypothalamo-pituitary development during embryogenesis is a highly complex process involving the interaction of a network of spatiotemporally regulated signaling molecules and transcription factors. Mutations in any of the genes encoding these components can lead to congenital hypopituitarism, which is often associated with a wide spectrum of defects affecting craniofacial/midline development. In turn, these defects can be incompatible with life, or lead to disorders encompassing holoprosencephaly (HPE) and cleft palate, and Septo-Optic Dysplasia (SOD). In recent years, there has been increasing evidence of an overlapping genotype between this spectrum of disorders and Kallmann syndrome (KS), defined as the association of hypogonadotropic hypogonadism (HH) and anosmia. This is consistent with the known phenotypic overlap between these disorders and opens a new avenue of identifying novel genetic causes of the hypopituitarism spectrum. This chapter reviews the genetic and molecular events leading to the successful development of the hypothalamo-pituitary axis during embryogenesis, and focuses on genes in which variations/mutations occur, leading to congenital hypopituitarism and associated defects.
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structural pituitary abnormalities associated with charge syndrome
The Journal of Clinical Endocrinology and Metabolism, 2013Co-Authors: Louise C Gregory, Mark J Mccabe, Ef Gevers, Dj Josifova, Joanne Baker, Tessa Kasia, Kling Chong, Maria Caimari, Frederic Bilan, Mehul T. DattaniAbstract:Introduction: CHARGE syndrome is a multisystem disorder that, in addition to Kallmann syndrome/isolated hypogonadotrophic hypogonadism, has been associated with anterior pituitary hypoplasia (APH). However, structural abnormalities such as an ectopic posterior pituitary (EPP) have not yet been described in such patients. Objective: The aims of the study were: 1) to describe the association between CHARGE syndrome and a structurally abnormal pituitary gland; and 2) to investigate whether CHD7 variants, which are identified in 65% of CHARGE patients, are common in Septo-Optic Dysplasia /hypopituitarism. Methods: We describe 2 patients with features of CHARGE and EPP. CHD7 was sequenced in these and other patients with Septo-Optic Dysplasia/hypopituitarism. Results: EPP, APH, and GH, TSH, and probable LH/FSH deficiency were present in 1 patient, and EPP and APH with GH, TSH, LH/FSH, and ACTH deficiency were present in another patient, both of whom had features of CHARGE syndrome. Both had variations in CHD7 ...
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pituitary gland development an update
Endocrine development, 2012Co-Authors: Rodrigo E Bancalari, Mark J Mccabe, Louise C Gregory, Mehul T. DattaniAbstract:The embryonic development of the pituitary gland involves a complex and highly spatio-temporally regulated network of integrating signalling molecules and transcription factors. Genetic mutations in any of these factors can lead to congenital hypopituitarism in association with a wide spectrum of craniofacial/midline defects ranging from incompatibility with life to holoprosencephaly (HPE) and cleft palate and Septo-Optic Dysplasia (SOD). Increasing evidence supports a genotypic overlap with hypogonadotrophic hypogonadal disorders such as Kallmann syndrome, which is consistent with the known overlap in phenotypes between these disorders. This chapter reviews the cascade of events leading up to the successful development of the pituitary gland and to highlight key areas where genetic variations can occur thus leading to congenital hypopituitarism and associated defects.
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growth hormone deficiency and related disorders insights into causation diagnosis and treatment
The Lancet, 2004Co-Authors: Mehul T. Dattani, M A PreeceAbstract:Advances in molecular biology have led to the identification of mutations within several novel genes associated with the phenotype of isolated growth hormone deficiency, combined pituitary hormone deficiency, and syndromes such as Septo-Optic Dysplasia. Progress has also been made in terms of the optimum diagnosis of disorders of stature and their treatment. The use of growth hormone for the treatment of adults with growth hormone deficiency and conditions such as Turner's syndrome, Prader-Willi syndrome, intrauterine growth restriction, and chronic renal failure has changed the practice of endocrinology, although cost-benefit implications remain to be established.
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Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and Septo-Optic Dysplasia
Human molecular genetics, 2001Co-Authors: Paul Q. Thomas, Joshua M Brickman, Mehul T. Dattani, David E. G. Mcnay, Garry L. Warne, Margaret Zacharin, Fergus J. Cameron, Jane A. Hurst, Katie A. Woods, David B. DungerAbstract:We have previously shown that familial Septo-Optic Dysplasia (SOD), a syndromic form of congenital hypopituitarism involving optic nerve hypoplasia and agenesis of midline brain structures, is associated with homozygosity for an inactivating mutation in the homeobox gene HESX1/Hesx1 in man and mouse. However, as most SOD/congenital hypopituitarism occurs sporadically, the possible contribution of HESX1 mutations to the aetiology of these cases is presently unclear. Interestingly, a small proportion of mice heterozygous for the Hesx1 null allele show a milder SOD phenocopy, implying that heterozygous mutations in human HESX1 could underlie some cases of congenital pituitary hypoplasia with or without midline defects. Accordingly, we have now scanned for HESX1 mutations in 228 patients with a broad spectrum of congenital pituitary defects, ranging in severity from isolated growth hormone deficiency to SOD with panhypopituitarism. Three different heterozygous missense mutations were detected in individuals with relatively mild pituitary hypoplasia or SOD, which display incomplete penetrance and variable phenotype amongst heterozygous family members. Gel shift analysis of the HESX1-S170L mutant protein, which is encoded by the C509T mutated allele, indicated that a significant reduction in relative DNA binding activity results from this mutation. Segregation analysis of a haplotype spanning 6.1 cM, which contains the HESX1 locus, indicated that only one HESX1 mutation was present in the families containing the C509T and A541G mutations. These results demonstrate that some sporadic cases of the more common mild forms of pituitary hypoplasia have a genetic basis, resulting from heterozygous mutation of the HESX1 gene.
Mark Borchert - One of the best experts on this subject based on the ideXlab platform.
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Optic Nerve Hypoplasia Syndrome: A Review of the Epidemiology and Clinical Associations
Current Treatment Options in Neurology, 2013Co-Authors: Pamela Garcia-filion, Mark BorchertAbstract:Background: Optic nerve hypoplasia (ONH) has developed into a leading cause of congenital blindness. The frequently associated features of hypopituitarism and absent septum pellucidum were felt to have embryonic linkage as “Septo-Optic Dysplasia” or “de Morsier’s syndrome.” More recent studies have suggested these associations are independent of one another. This review provides an assessment of the historical and recent evidence linking neuroradiologic, endocrinologic and developmental morbidity in patients with ONH. The prenatal risk factors, heritability, and genetic mutations associated with ONH are described. Results: Recognition of the critical association of ONH with hypopituitarism should be attributed to William Hoyt, not Georges de Morsier. De Morsier never described a case of ONH or recognized its association with hypopituitarism or missing septum pellucidum. Hypopituitarism is caused by hypothalamic dysfunction. This, and other more recently identified associations with ONH, such as developmental delay and autism, are independent of septum pellucidum development. Other common neuroradiographic associations such as corpus callosum hypoplasia, gyrus Dysplasia, and cortical heterotopia may have prognostic significance. The predominant prenatal risk factors for ONH are primiparity and young maternal age. Presumed risk factors such as prenatal exposure to drugs and alcohol are not supported by scrutiny of the literature. Heritability and identified gene mutations in cases of ONH are rare. Conclusion: Children with ONH require monitoring for many systemic, developmental, and even life-threatening problems independent of the severity of ONH and presence of brain malformations including abnormalities of the septum pellucidum. “Septo-Optic Dysplasia” and “de Morsier’s syndrome” are historically inaccurate and clinically misleading terms.
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reappraisal of the optic nerve hypoplasia syndrome
Journal of Neuro-ophthalmology, 2012Co-Authors: Mark BorchertAbstract:BackgroundOptic nerve hypoplasia (ONH) has been described as an increasingly prevalent cause of congenital blindness. Its association with hypopituitarism and absent septum pellucidum has been recognized for more than 40 years as “Septo-Optic Dysplasia” or “de Morsier syndrome.” More recent studies
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presenting features and long term effects of growth hormone treatment of children with optic nerve hypoplasia septo optic Dysplasia
International Journal of Pediatric Endocrinology, 2011Co-Authors: Amy Vedin, Mark Borchert, Cassandra Fink, Hanna Karlsson, Mitchell E GeffnerAbstract:Background: Optic nerve hypoplasia (ONH) with/or without Septo-Optic Dysplasia (SOD) is a known concomitant of congenital growth hormone deficiency (CGHD). Methods: Demographic and longitudinal data from KIGS, the Pfizer International Growth Database, were compared between 395 subjects with ONH/SOD and CGHD and 158 controls with CGHD without midline pathology. Results: ONH/SOD subjects had higher birth length/weight, and mid-parental height SDS. At GH start, height, weight, and BMI SDS were higher in the ONH/SOD group. After 1 year of GH, both groups showed similar changes in height SDS, while weight and BMI SDS remained higher in the ONH/SOD group. The initial height responses of the two groups were similar to those predicted using the KIGS-derived prediction model for children with idiopathic GHD. At near-adult height, ONH/SOD and controls had similar height, weight, and BMI SDS. Conclusions: Compared to children with CGHD without midline defects, those with ONH/SOD presented with greater height, weight, and BMI SDS. These differences persisted at 1 year of GH therapy, but appeared to be overcome by long-term GH treatment.
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The syndrome of optic nerve hypoplasia
Current Neurology and Neuroscience Reports, 2008Co-Authors: Mark Borchert, Pamela Garcia-filionAbstract:The congenital malformation known as optic nerve hypoplasia (ONH) has been recognized in the past 30 years as an epidemic cause of congenital blindness. It was believed to occur either as an isolated anomaly or as a component of the syndrome of Septo-Optic Dysplasia, which has evolved to include midline brain malformations and hypopituitarism. Evidence now suggests that ONH infrequently occurs in isolation. Most afflicted children will have hypothalamic dysfunction and/or neurodevelopmental impairment, regardless of MRI findings or severity of ONH. Adverse outcomes can often be ameliorated with early intervention. Thus, the syndrome of ONH should be suspected in all infants with signs of hypothalamic dysfunction or vision impairment.
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optic nerve hypoplasia and hypopituitarism
Pediatric endocrinology reviews, 2008Co-Authors: Tariq Ahmad, Mark Borchert, Mitchell E GeffnerAbstract:Optic nerve hypoplasia (ONH) has a wide clinical spectrum. When it is associated with absence of the septum pellucidum, it has been termed Septo-Optic Dysplasia. Over the past 50 years, much has been learned about ONH and its association with pituitary endocrinopathies. Causative factors have been sought that may disrupt development of the optic nerve and the hypothalamic-pituitary axis simultaneously. The endocrinological aspects of ONH require lifelong monitoring and replacement of pituitary hormones when necessary. Children with ONH are also at greater risk for structural abnormalities of the brain, and abnormalities in certain structures are positively correlated with increased risk for pituitary deficiencies. However, it has also been shown that children with ONH and "normal" head imaging can still manifest endocrinopathies. Subsequently, a long-term multidisciplinary approach, involving pediatric specialists in ophthalmology, endocrinology, neurology, and behavioral therapy, is critical to optimize growth and development of all children with ONH.
Vaitsa Tziaferi - One of the best experts on this subject based on the ideXlab platform.
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variations in prokr2 but not prok2 are associated with hypopituitarism and septo optic Dysplasia
The Journal of Clinical Endocrinology and Metabolism, 2013Co-Authors: Mark J Mccabe, Vaitsa Tziaferi, Carles Gastonmassuet, Louise C Gregory, Kyriaki S Alatzoglou, Oualid Sbai, Philippe Rondard, Kohhei Masumoto, Mamoru Nagano, Yasufumi ShigeyoshiAbstract:Context: Loss-of-function mutations in PROK2 and PROKR2 have been implicated in Kallmann syndrome (KS), characterized by hypogonadotropic hypogonadism and anosmia. Recent data suggest overlapping phenotypes/genotypes between KS and congenital hypopituitarism (CH), including Septo-Optic Dysplasia (SOD). Objective: We screened a cohort of patients with complex forms of CH (n = 422) for mutations in PROK2 and PROKR2. Results: We detected 5 PROKR2 variants in 11 patients with SOD/CH: novel p.G371R and previously reported p.A51T, p.R85L, p.L173R, and p.R268C—the latter 3 being known functionally deleterious variants. Surprisingly, 1 patient with SOD was heterozygous for the p.L173R variant, whereas his phenotypically unaffected mother was homozygous for the variant. We sought to clarify the role of PROKR2 in hypothalamopituitary development through analysis of Prokr2−/− mice. Interestingly, these revealed predominantly normal hypothalamopituitary development and terminal cell differentiation, with the exceptio...
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genetic overlap in kallmann syndrome combined pituitary hormone deficiency and septo optic Dysplasia
The Journal of Clinical Endocrinology and Metabolism, 2012Co-Authors: Taneli Raivio, Andrew A Dwyer, Magdalena Avbelj, Christopher J Romero, Daniel Diaczok, Gerasimos P. Sykiotis, Johanna Tommiska, Mark J Mccabe, Louise C Gregory, Vaitsa TziaferiAbstract:Context: Kallmann syndrome (KS), combined pituitary hormone deficiency (CPHD), and Septo-Optic Dysplasia (SOD) all result from development defects of the anterior midline in the human forebrain. Objective: The objective of the study was to investigate whether KS, CPHD, and SOD have shared genetic origins. Design and Participants: A total of 103 patients with either CPHD (n = 35) or SOD (n = 68) were investigated for mutations in genes implicated in the etiology of KS (FGFR1, FGF8, PROKR2, PROK2, and KAL1). Consequences of identified FGFR1, FGF8, and PROKR2 mutations were investigated in vitro. Results: Three patients with SOD had heterozygous mutations in FGFR1; these were either shown to alter receptor signaling (p.S450F, p.P483S) or predicted to affect splicing (c.336C>T, p.T112T). One patient had a synonymous change in FGF8 (c.216G>A, p.T72T) that was shown to affect splicing and ligand signaling activity. Four patients with CPHD/SOD were found to harbor heterozygous rare loss-of-function variants in P...
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novel fgf8 mutations associated with recessive holoprosencephaly craniofacial defects and hypothalamo pituitary dysfunction
The Journal of Clinical Endocrinology and Metabolism, 2011Co-Authors: Mark J Mccabe, Vaitsa Tziaferi, Massimo Signore, Eduardo Puelles, Dianne Gerrelli, Sadaf I Farooqi, Carles Gastonmassuet, Louise C Gregory, Kyriaki S Alatzoglou, Jamal RazaAbstract:Context: Fibroblast growth factor (FGF) 8 is important for GnRH neuronal development with human mutations resulting in Kallmann syndrome. Murine data suggest a role for Fgf8 in hypothalamo-pituitary development; however, its role in the etiology of wider hypothalamo-pituitary dysfunction in humans is unknown.Objective: The objective of this study was to screen for FGF8 mutations in patients with Septo-Optic Dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47).Methods: FGF8 was analyzed by PCR and direct sequencing. Ethnically matched controls were then screened for mutated alleles (n = 480-686). Localization of Fgf8/FGF8 expression was analyzed by in situ hybridization in developing murine and human embryos. Finally, Fgf8 hypomorphic mice (Fgf8(loxPNeo/-)) were analyzed for the presence of forebrain and hypothalamo-pituitary defects.Results: A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. Second, a heterozygous p.Q216E mutation was identified in a female patient with an absent corpus callosum, hypoplastic optic nerves, and Moebius syndrome. FGF8 was expressed in the ventral diencephalon and anterior commissural plate but not in Rathke's pouch, strongly suggesting early onset hypothalamic and corpus callosal defects in these patients. This was consolidated by significantly reduced vasopressin and oxytocin staining neurons in the hypothalamus of Fgf8 hypomorphic mice compared with controls along with variable hypothalamo-pituitary defects and HPE.Conclusion: We implicate FGF8 in the etiology of recessive HPE and potentially Septo-Optic Dysplasia/Moebius syndrome for the first time to our knowledge. Furthermore, FGF8 is important for the development of the ventral diencephalon, hypothalamus, and pituitary. (J Clin Endocrinol Metab 96: E1709-E1718, 2011)
