Expanding the Phenotypic Spectrum and Variability of Endocrine Abnormalities Associated With TUBB3 E410K Syndrome

Balasubramanian, Ravikumar; Chew, Sheena; MacKinnon, Sarah; Kang, Peter B.; Andrews, Caroline; Chan, Wai Man; Engle, Elizabeth C.

doi:10.1210/jc.2014-4107

Cited by 21 publications

(9 citation statements)

References 12 publications

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“…However, in 2015, a female patient with a E410K mutation in TUBB3 was identified and exhibited normal fertility yet displayed all other features of the E410K syndrome, including anosmia. This heterozygous mutation was inherited by her three sons, as well as variable features of additional endocrine abnormalities (Balasubramanian et al, 2015). Tubb3 KO mice show no notable neurobehavioral or neuropathological deficits that overlap with above described patient (Latremoliere et al, 2018).…”

Section: Spectrum Of Genetic Disorders In Gnrh Cell Deficiency and Kamentioning

confidence: 99%

Nasal Placode Development, GnRH Neuronal Migration and Kallmann Syndrome

Cho

Shan

Whittington

et al. 2019

Front. Cell Dev. Biol.

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The development of Gonadotropin releasing hormone-1 (GnRH) neurons is important for a functional reproduction system in vertebrates. Disruption of GnRH results in hypogonadism and if accompanied by anosmia is termed Kallmann Syndrome (KS). From their origin in the nasal placode, GnRH neurons migrate along the olfactory-derived vomeronasal axons to the nasal forebrain junction and then turn caudally into the developing forebrain. Although research on the origin of GnRH neurons, their migration and genes associated with KS has identified multiple factors that influence development of this system, several aspects still remain unclear. This review discusses development of the olfactory system, factors that regulate GnRH neuron formation and development of the olfactory system, migration of the GnRH neurons from the nose into the brain, and mutations in humans with KS that result from disruption of normal GnRH/olfactory systems development.

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Section: Spectrum Of Genetic Disorders In Gnrh Cell Deficiency and Kamentioning

confidence: 99%

Nasal Placode Development, GnRH Neuronal Migration and Kallmann Syndrome

Cho

Shan

Whittington

et al. 2019

Front. Cell Dev. Biol.

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“…The discovery of a novel KS candidate gene is not unprecedented as discovering genetic overlapping syndromes had already lead to novel genetic insights. Genetic insights have been gleaned from studies examining overlaps between CHH/KS and Hartsfield syndrome (split hand-foot) [79,80], Bosma arhinia syndrome [81], combined pituitary hormone deficiency/septo-optic dysplasia [82], holoprosencephaly (12,16,22 and OMIM 610828) Moebius syndrome [83], adrenal hypoplasia congenita [84] and Gordon-Holmes syndrome [85], Waardenburg syndrome [7], and CHARGE syndrome [5,6]. Mutations in CHD7 are identified in approximately 60% of CHARGE cases (range 33-100%) [86].…”

Section: Discussionmentioning

confidence: 99%

Congenital Hypogonadotropic Hypogonadism with Anosmia and Gorlin Features Caused by a PTCH1 Mutation Reveals a New Candidate Gene for Kallmann Syndrome

et al. 2020

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Background: Two loci (CHD7 and SOX10) underlying Kallmann syndrome (KS) were discovered through clinical and genetic analysis of CHARGE and Waardenburg syndromes, conditions that include congenital anosmia caused by olfactory bulb (CA/OBs) defects and congenital hypogonadotropic hypogonadism (CHH). We hypothesized that other candidate genes for KS could be discovered by analyzing rare syndromes presenting with these signs. Study Design, Size, Duration: We first investigated a family with Gorlin-Goltz syndrome (GGS) in which affected members exhibited clinical signs suggesting KS. Participants/Materials, Methods: Proband and family members underwent detailed clinical assessment. The proband received detailed neuroendocrine evaluation. Genetic analyses included sequencing the PTCH1 gene at diagnosis, followed by exome analyses of causative or candidate KS/CHH genes, in order to exclude contribution to the phenotypes of additional mutations. Exome analyses in additional 124 patients with KS/CHH probands with no additional GGS signs. Results: The proband exhibited CA, absent OBs on magnetic resonance imaging, and had CHH with unilateral cryptorchidism, consistent with KS. Pulsatile Gonadotropin-releasing hormone (GnRH) therapy normalized serum gonadotropins and increased testosterone levels, supporting GnRH deficiency. Genetic studies revealed 3 affected family members harbor a novel mutation of PTCH1 (c.838G> T; p.Glu280*). This unreported nonsense deleterious mutation results in either a putative truncated Ptch1 protein or in an absence of translated Ptch1 protein related to nonsense mediated messenger RNA decay. This heterozygous mutation cosegregates in the pedigree with GGS and CA with OBs aplasia/hypoplasia and with CHH in the proband suggesting a genetic linkage and an autosomal dominant mode of inheritance. No pathogenic rare variants in other KS/CHH genes cosegregated with these phenotypes. In additional 124 KS/CHH patients, 3 additional heterozygous, rare missense variants were found and predicted in silico to be damaging: p.Ser1203Arg, p.Arg1192Ser, and p.Ile108Met. Conclusion: This family suggests that the 2 main signs of KS can be included in GGS associated with PTCH1 mutations. Our data combined with mice models suggest that PTCH1 could be a novel candidate gene for KS/CHH and reinforce the role of the Hedgehog signaling pathway in pathophysiology of KS and GnRH neuron migration.

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“…For example, whole-exome sequencing analysis in patients with Gordon Holmes syndrome (IGD and cerebellar ataxia) led to the discovery of ovarian tumor deubiquitinase 4 gene (OTUD4) and ring finger protein 216 (RNF216) (53), as well as mutations in stress-induced phosphoprotein 1 homology and U-box containing protein 1, E3 ubiquitin protein ligase (STUB1) and patatin-like phospholipase domain-containing protein 6 (PNPLA6) (54) that were found in IGD patients who also displayed ataxia (55). There are also several other genes causing 4H syndrome (hypomyelination, hypodontia and hypogonadotropic hypogonadism), including polymerase III, RNA subunit A and B (POLR3A and POLR3B) (56, 57) Additionally, a novel clinical syndrome defined by a specific genetic mutation in the neuronal tubulin-b class 3 (TUBB3) gene was recently described having the characteristics of Moebius syndrome (facial hypoplasia/paralysis and oculomotor defects) accompanied by KS, intellectual disabilities, and in some cases, vocal cord paralysis, tracheomalacia, and cyclical vomiting (58)(59)(60). In the future, it is likely that such pleiotropic genes will be associated with the nonsyndromic form of IGD as well.…”

Section: B Phenotypic Complexity Identifies Pleiotropic Genes In Synmentioning

confidence: 99%

Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the “-Omics” Era

2015

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The neuroendocrine regulation of reproduction is an intricate process requiring the exquisite coordination of an assortment of cellular networks, all converging on the GnRH neurons. These neurons have a complex life history, migrating mainly from the olfactory placode into the hypothalamus, where GnRH is secreted and acts as the master regulator of the hypothalamicpituitary-gonadal axis. Much of what we know about the biology of the GnRH neurons has been aided by discoveries made using the human disease model of isolated GnRH deficiency (IGD), a family of rare Mendelian disorders that share a common failure of secretion and/or action of GnRH causing hypogonadotropic hypogonadism. Over the last 30 years, research groups around the world have been investigating the genetic basis of IGD using different strategies based on complex cases that harbor structural abnormalities or single pleiotropic genes, endogamous pedigrees, candidate gene approaches as well as pathway gene analyses. Although such traditional approaches, based on well-validated tools, have been critical to establish the field, new strategies, such as next-generation sequencing, are now providing speed and robustness, but also revealing a surprising number of variants in known IGD genes in both patients and healthy controls. Thus, before the field moves forward with new genetic tools and continues discovery efforts, we must reassess what we know about IGD genetics and prepare to hold our work to a different standard. The purpose of this review is to: 1) look back at the strategies used to discover the "known" genes implicated in the rare forms of IGD; 2) examine the strengths and weaknesses of the methodologies used to validate genetic variation; 3)substantiate the role of known genes in the pathophysiology of the disease; and 4) project forward as we embark upon a widening use of these new and powerful technologies for gene discovery.

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Expanding the Phenotypic Spectrum and Variability of Endocrine Abnormalities Associated With TUBB3 E410K Syndrome

Cited by 21 publications

References 12 publications

Nasal Placode Development, GnRH Neuronal Migration and Kallmann Syndrome

Nasal Placode Development, GnRH Neuronal Migration and Kallmann Syndrome

Congenital Hypogonadotropic Hypogonadism with Anosmia and Gorlin Features Caused by a PTCH1 Mutation Reveals a New Candidate Gene for Kallmann Syndrome

Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the “-Omics” Era

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