scholarly journals A novel SOX10 nonsense mutation in a patient with Kallmann syndrome and Waardenburg syndrome

2021 ◽  
Vol 2021 ◽  
Author(s):  
Tetsuji Wakabayashi ◽  
Akihito Takei ◽  
Nobukazu Okada ◽  
Miki Shinohara ◽  
Manabu Takahashi ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Neural Crest ◽  
Nonsense Mutation ◽  
Hypogonadotropic Hypogonadism ◽  
Neural Crest Cells ◽  
Kallmann Syndrome ◽  
List Type ◽  
Waardenburg Syndrome ◽  
Common Pathway ◽  
Causative Gene

Summary The underlying genetic drivers of Kallmann syndrome, a rare genetic disorder characterized by anosmia and hypogonadotropic hypogonadism due to impairment in the development of olfactory axons and in the migration of gonadotropin-releasing hormone (GNRH)-producing neurons during embryonic development, remain largely unknown. SOX10, a key transcription factor involved in the development of neural crest cells and established as one of the causative genes of Waardenburg syndrome, has been shown to be a causative gene of Kallmann syndrome. A 17-year-old male patient, who was diagnosed with Waardenburg syndrome on the basis of a hearing impairment and hypopigmented iris at childhood, was referred to our department because of anosmia and delayed puberty. As clinical examination revealed an aplastic olfactory bulb and hypogonadotropic hypogonadism, we diagnosed him as having Kallmann syndrome. Incidentally, we elucidated that he also presented with subclinical hypothyroidism without evidence of autoimmune thyroiditis. Direct sequence analysis detected a nonsense SOX10 mutation (c.373C>T, p.Glu125X) in this patient. Since this nonsense mutation has never been published as a germline variant, the SOX10 substitution is a novel mutation that results in Kallmann syndrome and Waardenburg syndrome. This case substantiates the significance of SOX10 as a genetic cause of Kallmann syndrome and Waardenburg syndrome, which possibly share a common pathway in the development of neural crest cells. Learning points Kallmann syndrome and Waardenburg syndrome possibly share a common pathway during neural crest cell development. SOX10, a key transcription factor involved in the development of neural crest cells, is a common causative gene of Kallmann syndrome and Waardenburg syndrome. Careful evaluation about various phenotypic features may reveal the unknown genetic drivers of Kallmann syndrome.

scholarly journals Lineage-specific requirements of β-catenin in neural crest development

2002 ◽  
Vol 159 (5) ◽  
pp. 867-880 ◽  
Author(s):  
Lisette Hari ◽  
Véronique Brault ◽  
Maurice Kléber ◽  
Hye-Youn Lee ◽  
Fabian Ille ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Neural Crest ◽  
Neural Crest Cells ◽  
Neural Crest Stem Cells ◽  
Downstream Signaling ◽  
Neural Crest Development ◽  
Sensory Neurogenesis

β-Catenin plays a pivotal role in cadherin-mediated cell adhesion. Moreover, it is a downstream signaling component of Wnt that controls multiple developmental processes such as cell proliferation, apoptosis, and fate decisions. To study the role of β-catenin in neural crest development, we used the Cre/loxP system to ablate β-catenin specifically in neural crest stem cells. Although several neural crest–derived structures develop normally, mutant animals lack melanocytes and dorsal root ganglia (DRG). In vivo and in vitro analyses revealed that mutant neural crest cells emigrate but fail to generate an early wave of sensory neurogenesis that is normally marked by the transcription factor neurogenin (ngn) 2. This indicates a role of β-catenin in premigratory or early migratory neural crest and points to heterogeneity of neural crest cells at the earliest stages of crest development. In addition, migratory neural crest cells lateral to the neural tube do not aggregate to form DRG and are unable to produce a later wave of sensory neurogenesis usually marked by the transcription factor ngn1. We propose that the requirement of β-catenin for the specification of melanocytes and sensory neuronal lineages reflects roles of β-catenin both in Wnt signaling and in mediating cell–cell interactions.

Chick Sox10, a transcription factor expressed in both early neural crest cells and central nervous system

2000 ◽  
Vol 121 (2) ◽  
pp. 233-241 ◽  
Author(s):  
Yi-Chuan Cheng ◽  
Martin Cheung ◽  
Muhammad M. Abu-Elmagd ◽  
Alex Orme ◽  
Paul J. Scotting
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Transcription Factor ◽  
Neural Crest ◽  
Neural Crest Cells

scholarly journals A novel SOX10 variant in a Japanese girl with Waardenburg syndrome type 4C and Kallmann syndrome

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Junpei Hamada ◽  
Fumihiro Ochi ◽  
Yuka Sei ◽  
Koji Takemoto ◽  
Hiroki Hirai ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Hypogonadotropic Hypogonadism ◽  
Hirschsprung Disease ◽  
Kallmann Syndrome ◽  
Syndrome Type ◽  
Waardenburg Syndrome ◽  
First Case ◽  
Iris Depigmentation ◽  
Bilateral Sensorineural Hearing Loss

AbstractWe report the first case of Waardenburg syndrome type 4C and Kallmann syndrome in the same person. The patient, a Japanese girl, presented with bilateral iris depigmentation, bilateral sensorineural hearing loss, Hirschsprung disease, hypogonadotropic hypogonadism, and anosmia. We identified a novel SOX10 variant, c.124delC, p.Leu42Cysfs*67.

scholarly journals Parallel Multi-Gene Panel Testing for Diagnosis of Idiopathic Hypogonadotropic Hypogonadism/Kallmann Syndrome

2019 ◽  
Vol 2019 ◽  
pp. 1-3 ◽  
Author(s):  
Manickavasagam Senthilraja ◽  
Aaron Chapla ◽  
Felix K. Jebasingh ◽  
Dukhabhandhu Naik ◽  
Thomas V. Paul ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Hypogonadotropic Hypogonadism ◽  
Cost Effective ◽  
Kallmann Syndrome ◽  
Causative Gene ◽  
Idiopathic Hypogonadotropic Hypogonadism ◽  
Panel Testing ◽  
Kal1 Gene ◽  
Gene Panel Testing ◽  
The Subject

Kallmann syndrome (KS)/Idiopathic hypogonadotropic hypogonadism (IHH) is characterized by hypogonadotropic hypogonadism and anosmia or hyposmia due to the abnormal migration of olfactory and gonadotropin releasing hormone producing neurons. Multiple genes have been implicated in KS/IHH. Sequential testing of these genes utilising Sanger sequencing is time consuming and not cost effective. The introduction of parallel multigene panel sequencing of small gene panels for the identification of causative gene variants has been shown to be a robust tool in the clinical setting. Utilizing multiplex PCR for the four gene KS/IHH panel followed by NGS, we describe herewith two cases of hypogonadotropic hypogonadism with a Prokineticin receptor 2 (PROKR2) gene and KAL1 gene mutation. The subject with a PROKR2 mutation had a normal perception of smell and normal olfactory bulbs on imaging. The subject with a KAL1 gene mutation had anosmia and a hypoplastic olfactory bulb.

scholarly journals Kallmann Syndrome Due to Heterozygous Mutation in SOX10 Coexisting With Waardenburg Syndrome Type II: Case Report and Review of Literature

2021 ◽  
Vol 11 ◽  
Author(s):  
Kan Chen ◽  
Haoyu Wang ◽  
Yaxin Lai
Keyword(s):  
Amino Acid ◽  
Pituitary Gland ◽  
Sequence Data ◽  
Hypogonadotropic Hypogonadism ◽  
Clinical Manifestations ◽  
Kallmann Syndrome ◽  
Syndrome Type ◽  
Type Ii ◽  
Waardenburg Syndrome ◽  
Pathogenic Gene

IntroductionKallmann syndrome (KS) is idiopathic hypogonadotropic hypogonadism with olfactory loss or decline. Waardenburg syndrome type II (WS2) is a clinically and genetically heterogeneous disease, characterized by congenital sensorineural deafness and abnormal pigmentation of the iris, hair, and skin. Recently, mutations in the well-known WS pathogenic gene SOX10 have been found in some KS patients with deafness, but whether SOX10 is a co-pathogenic gene of KS and WS remains uncertain. Here, we report a rare case of KS and WS2 co-occurrence due to SOX10 mutations.MethodsDetailed histories were collected through questionnaires and physical examination. Blood samples of the patient and his family members were collected after obtaining informed consents. Suspected mutations were amplified and verified by Sanger sequencing after the next generation sequencing of related genes. The raw sequence data were compared to the known gene sequence data in publicly available sequence data bases using Burrows-Wheeler Aligner software (BWA, 0.7.12-r1039).ResultsA 28-year-old male patient sought treatment for hypogonadism and the absence of secondary sexual characteristics. In addition, he showed signs of obesity, hyposmia, sensorineural hearing loss, and blue iris. Magnetic resonance imaging (MRI) of the olfactory bulb showed small bilateral olfactory bulbs and tracts and diaphragma cerebri. MRI of the pituitary gland revealed a flat pituitary gland in the sella. Laboratory examination demonstrated hypogonadotropic hypogonadism, pituitary hypothyroidism, subclinical hypothyroidism, and the presence of insulin resistance with normal blood glucose levels. Sequencing of the SOX10 gene showed a 20 bp insertion in between coding bases 1,179 and 1,180 (c.1179_1180insACTATGGCTCAGCCTTCCCC). This results in a frame-shifting mutation of the 394th amino acid serine in exon4 with the resulting the amino acid sequence of the protein predicted to be TMAQPSP PSPAPSLTTL TISPQDPIMA TRARPLASTR PSPIWGPRSG PSTRPSLTPA PQGPSPTAPH TGSSQYIRHC PGPKGGPVAT TPRPAPAPSL CALFLAHLRP GGGSGGG*.ConclusionSOX10 plays an important role in some critical stages of neural crest cell development and SOX10 mutation may be a common pathogenic factor for both KS and WS. Therefore, SOX10 mutation analysis should be considered for KS patients with combined WS clinical manifestations, especially deafness.

The winged-helix transcription factor Foxd3 suppresses interneuron differentiation and promotes neural crest cell fate

Development ◽  
2001 ◽  
Vol 128 (21) ◽  
pp. 4127-4138 ◽  
Author(s):  
Mirella Dottori ◽  
Michael K. Gross ◽  
Patricia Labosky ◽  
Martyn Goulding
Keyword(s):  
Transcription Factor ◽  
Neural Crest ◽  
Cell Fate ◽  
Neural Tube ◽  
Neural Crest Cell ◽  
Neural Crest Cells ◽  
Cell Types ◽  
Winged Helix ◽  
Multiple Cell ◽  
Winged Helix Transcription Factor

The neural crest is a migratory cell population that gives rise to multiple cell types in the vertebrate embryo. The intrinsic determinants that segregate neural crest cells from multipotential dorsal progenitors within the neural tube are poorly defined. In this study, we show that the winged helix transcription factor Foxd3 is expressed in both premigratory and migratory neural crest cells. Foxd3 is genetically downstream of Pax3 and is not expressed in regions of Pax3 mutant mice that lack neural crest, implying that Foxd3 may regulate aspects of the neural crest differentiation program. We show that misexpression of Foxd3 in the chick neural tube promotes a neural crest-like phenotype and suppresses interneuron differentiation. Cells that ectopically express Foxd3 upregulate HNK1 and Cad7, delaminate and emigrate from the neural tube at multiple dorsoventral levels. Foxd3 does not induce Slug and RhoB, nor is its ability to promote a neural crest-like phenotype enhanced by co-expression of Slug. Together these results suggest Foxd3 can function independently of Slug and RhoB to promote the development of neural crest cells from neural tube progenitors.

scholarly journals Upregulation of theNr2f1-A830082K12Rikgene pair in murine neural crest cells results in a complex phenotype reminiscent of Waardenburg syndrome type 4

2016 ◽  
Vol 9 (11) ◽  
pp. 1283-1293 ◽  
Author(s):  
Karl-F. Bergeron ◽  
Chloé M. A. Nguyen ◽  
Tatiana Cardinal ◽  
Baptiste Charrier ◽  
David W. Silversides ◽  
...  
Keyword(s):  
Neural Crest ◽  
Neural Crest Cells ◽  
Syndrome Type ◽  
Waardenburg Syndrome ◽  
Complex Phenotype
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