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Journal of Medical Genetics Feb 2022SOX10 belongs to a family of 20 SRY (sex-determining region Y)-related high mobility group box-containing (SOX) proteins, most of which contribute to cell type... (Review)
Review
SOX10 belongs to a family of 20 SRY (sex-determining region Y)-related high mobility group box-containing (SOX) proteins, most of which contribute to cell type specification and differentiation of various lineages. The first clue that SOX10 is essential for development, especially in the neural crest, came with the discovery that heterozygous mutations occurring within and around SOX10 cause Waardenburg syndrome type 4. Since then, heterozygous mutations have been reported in Waardenburg syndrome type 2 (Waardenburg syndrome type without Hirschsprung disease), PCWH or PCW (peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, with or without Hirschsprung disease), intestinal manifestations beyond Hirschsprung (ie, chronic intestinal pseudo-obstruction), Kallmann syndrome and cancer. All of these diseases are consistent with the regulatory role of SOX10 in various neural crest derivatives (melanocytes, the enteric nervous system, Schwann cells and olfactory ensheathing cells) and extraneural crest tissues (inner ear, oligodendrocytes). The recent evolution of medical practice in constitutional genetics has led to the identification of variants in atypical contexts, such as isolated hearing loss or neurodevelopmental disorders, making them more difficult to classify in the absence of both a typical phenotype and specific expertise. Here, we report novel mutations and review those that have already been published and their functional consequences, along with current understanding of SOX10 function in the affected cell types identified through in vivo and in vitro models. We also discuss research options to increase our understanding of the origin of the observed phenotypic variability and improve the diagnosis and medical care of affected patients.
Topics: Animals; Embryonic Development; Enteric Nervous System; Gene Expression Regulation, Developmental; Hearing Loss; Hirschsprung Disease; Humans; Kallmann Syndrome; Melanocytes; Mutation; Neoplasms; Neural Crest; Phenotype; SOXE Transcription Factors; Waardenburg Syndrome
PubMed: 34667088
DOI: 10.1136/jmedgenet-2021-108105 -
The Journal of Clinical Endocrinology... Jul 2020Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation and neural crest tumor (ROHHHAD[NET]) is a rare and potentially fatal...
CONTEXT
Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation and neural crest tumor (ROHHHAD[NET]) is a rare and potentially fatal disease. No specific diagnostic biomarker is currently available, making prompt diagnosis challenging. Since its first definition in 2007, a complete clinical analysis leading to specific diagnosis and follow-up recommendations is still missing.
OBJECTIVE
The purpose of this work is to describe the clinical timeline of symptoms of ROHHAD(NET) and propose recommendations for diagnosis and follow-up.
DESIGN
We conducted a systematic review of all ROHHAD(NET) case studies and report a new ROHHAD patient with early diagnosis and multidisciplinary care.
METHODS
All the articles that meet the definition of ROHHAD(NET) and provide chronological clinical data were reviewed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis individual patient data guidelines. The data were grouped into 7 categories: hypothalamic dysfunction, autonomic dysregulation, hypoventilation, NET, psychiatric symptoms, other clinical manifestations, and outcome.
RESULTS
Forty-three individual patient data descriptions were analyzed. The timeline of the disease shows rapid-onset obesity followed shortly by hypothalamic dysfunction. Dysautonomia was reported at a median age of 4.95 years and hypoventilation at 5.33 years, or 2.2 years after the initial obesity. A NET was reported in 56% of the patients, and 70% of these tumors were diagnosed within 2 years after initial weight gain.
CONCLUSION
Because early diagnosis improves the clinical management and the prognosis in ROHHAD(NET), this diagnosis should be considered for any child with rapid and early obesity. We propose guidance for systematic follow-up and advise multidisciplinary management with the aim of improving prognosis and life expectancy.
Topics: Adrenal Gland Neoplasms; Autonomic Nervous System Diseases; Ganglioneuroblastoma; Ganglioneuroma; Humans; Hypothalamic Diseases; Hypoventilation; Obesity; Prognosis; Syndrome
PubMed: 32407531
DOI: 10.1210/clinem/dgaa247 -
Cold Spring Harbor Perspectives in... Jan 2021Cardiac neural crest (CNC) cells are pluripotent cells derived from the dorsal neural tube that migrate and contribute to the remodeling of pharyngeal arch arteries and... (Review)
Review
Cardiac neural crest (CNC) cells are pluripotent cells derived from the dorsal neural tube that migrate and contribute to the remodeling of pharyngeal arch arteries and septation of the cardiac outflow tract (OFT). Numerous molecular cascades regulate the induction, specification, delamination, and migration of the CNC. Extensive analyses of the CNC ranging from chick ablation models to molecular biology studies have explored the mechanisms of heart development and disease, particularly involving the OFT and aortic arch (AA) system. Recent studies focus more on reciprocal signaling between the CNC and cells originated from the second heart field (SHF), which are essential for the development of the OFT myocardium, providing new insights into the molecular mechanisms underlying congenital heart diseases (CHDs) and some human syndromes.
Topics: 22q11 Deletion Syndrome; Animals; Aorta, Thoracic; Cell Lineage; Cell Movement; Chick Embryo; Gene Deletion; Gene Expression Profiling; Heart; Heart Defects, Congenital; Humans; Myocardium; Neural Crest; Signal Transduction
PubMed: 32071091
DOI: 10.1101/cshperspect.a036715 -
Journal of Clinical Medicine Mar 2022Myelodysplastic syndrome (MDS) is a group of clonal disorders that arise in pluripotent bone marrow stem cells and present with characteristic phenotypical features...
Myelodysplastic syndrome (MDS) is a group of clonal disorders that arise in pluripotent bone marrow stem cells and present with characteristic phenotypical features (both morphological and flow cytometrical), as well as genotypical abnormalities [...].
PubMed: 35329932
DOI: 10.3390/jcm11061606 -
Journal of Medical Genetics Aug 1997Auditory-pigmentary syndromes are caused by physical absence of melanocytes from the skin, hair, eyes, or the stria vascularis of the cochlea. Dominantly inherited... (Review)
Review
Auditory-pigmentary syndromes are caused by physical absence of melanocytes from the skin, hair, eyes, or the stria vascularis of the cochlea. Dominantly inherited examples with patchy depigmentation are usually labelled Waardenburg syndrome (WS). Type I WS, characterised by dystopia canthorum, is caused by loss of function mutations in the PAX3 gene. Type III WS (Klein-Waardenburg syndrome, with abnormalities of the arms) is an extreme presentation of type I; some but not all patients are homozygotes. Type IV WS (Shah-Waardenburg syndrome with Hirschsprung disease) can be caused by mutations in the genes for endothelin-3 or one of its receptors, EDNRB. Type II WS is a heterogeneous group, about 15% of whom are heterozygous for mutations in the MITF (microphthalmia associated transcription factor) gene. All these forms show marked variability even within families, and at present it is not possible to predict the severity, even when a mutation is detected. Characterising the genes is helping to unravel important developmental pathways in the neural crest and its derivatives.
Topics: Endothelin-3; Eye Color; Face; Female; Homozygote; Humans; Incidence; Male; Prevalence; Receptors, Endothelin; Waardenburg Syndrome
PubMed: 9279758
DOI: 10.1136/jmg.34.8.656 -
Current Issues in Molecular Biology Dec 2023The embryonic development of neural crest cells and subsequent tissue differentiation are intricately regulated by specific transcription factors. Among these, , a... (Review)
Review
The embryonic development of neural crest cells and subsequent tissue differentiation are intricately regulated by specific transcription factors. Among these, , a member of the gene family, stands out. Located on chromosome 22q13, the gene encodes a transcription factor crucial for the differentiation, migration, and maintenance of tissues derived from neural crest cells. It plays a pivotal role in developing various tissues, including the central and peripheral nervous systems, melanocytes, chondrocytes, and odontoblasts. Mutations in have been associated with congenital disorders such as Waardenburg-Shah Syndrome, PCWH syndrome, and Kallman syndrome, underscoring its clinical significance. Furthermore, SOX10 is implicated in neural and neuroectodermal tumors, such as melanoma, malignant peripheral nerve sheath tumors (MPNSTs), and schwannomas, influencing processes like proliferation, migration, and differentiation. In mesenchymal tumors, SOX10 expression serves as a valuable marker for distinguishing between different tumor types. Additionally, SOX10 has been identified in various epithelial neoplasms, including breast, ovarian, salivary gland, nasopharyngeal, and bladder cancers, presenting itself as a potential diagnostic and prognostic marker. However, despite these associations, further research is imperative to elucidate its precise role in these malignancies.
PubMed: 38132479
DOI: 10.3390/cimb45120633 -
Developmental Dynamics : An Official... Aug 2020Mutations in core components of the spliceosome are responsible for a group of syndromes collectively known as spliceosomopathies. Patients exhibit microcephaly,... (Review)
Review
Mutations in core components of the spliceosome are responsible for a group of syndromes collectively known as spliceosomopathies. Patients exhibit microcephaly, micrognathia, malar hypoplasia, external ear anomalies, eye anomalies, psychomotor delay, intellectual disability, limb, and heart defects. Craniofacial malformations in these patients are predominantly found in neural crest cells-derived structures of the face and head. Mutations in eight genes SNRPB, RNU4ATAC, SF3B4, PUF60, EFTUD2, TXNL4, EIF4A3, and CWC27 are associated with craniofacial spliceosomopathies. In this review, we provide a brief description of the normal development of the head and the face and an overview of mutations identified in genes associated with craniofacial spliceosomopathies. We also describe a model to explain how and when these mutations are most likely to impact neural crest cells. We speculate that mutations in a subset of core splicing factors lead to disrupted splicing in neural crest cells because these cells have increased sensitivity to inefficient splicing. Hence, disruption in splicing likely activates a cellular stress response that includes increased skipping of regulatory exons in genes such as MDM2 and MDM4, key regulators of P53. This would result in P53-associated death of neural crest cells and consequently craniofacial malformations associated with spliceosomopathies.
Topics: Animals; Cell Cycle Proteins; Choanal Atresia; Craniofacial Abnormalities; Cyclophilins; DEAD-box RNA Helicases; Deafness; Disease Models, Animal; Eukaryotic Initiation Factor-4A; Exons; Facies; Heart Defects, Congenital; Humans; Intellectual Disability; Mice; Microcephaly; Micrognathism; Mutation; Neural Crest; Neuroepithelial Cells; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2; Psychomotor Disorders; RNA Splicing Factors; Ribonucleoprotein, U5 Small Nuclear; Spliceosomes; Syndrome; Tumor Suppressor Protein p53
PubMed: 32315467
DOI: 10.1002/dvdy.183 -
Cell Cycle (Georgetown, Tex.) Aug 2021Melanoma is the deadliest form of skin cancer. While clinical developments have significantly improved patient prognosis, effective treatment is often obstructed by... (Review)
Review
Melanoma is the deadliest form of skin cancer. While clinical developments have significantly improved patient prognosis, effective treatment is often obstructed by limited response rates, intrinsic or acquired resistance to therapy, and adverse events. Melanoma initiation and progression are associated with transcriptional reprogramming of melanocytes to a cell state that resembles the lineage from which the cells are specified during development, that is the neural crest. Convergence to a neural crest cell (NCC)-like state revealed the therapeutic potential of targeting developmental pathways for the treatment of melanoma. Neural crest cells have a unique sensitivity to metabolic dysregulation, especially nucleotide depletion. Mutations in the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH) particularly affect neural crest-derived tissues and cause Miller syndrome, a genetic disorder characterized by craniofacial malformations in patients. The developmental susceptibility of the neural crest to nucleotide deficiency is conserved in melanoma and provides a metabolic vulnerability that can be exploited for therapeutic purposes. We review the current knowledge on nucleotide stress responses in neural crest and melanoma and discuss how the recent scientific advances that have improved our understanding of transcriptional regulation during nucleotide depletion can impact melanoma treatment.
Topics: Animals; Antimetabolites, Antineoplastic; Cell Lineage; Gene Expression Regulation, Neoplastic; Humans; Melanocytes; Melanoma; Neural Crest; Nucleotides; Skin Neoplasms; Stress, Physiological; Transcription, Genetic
PubMed: 34281491
DOI: 10.1080/15384101.2021.1947567 -
Gene Aug 2018The PAX3 gene encodes a member of the PAX family of transcription factors that is characterized by a highly conserved paired box motif. The PAX3 protein is a... (Review)
Review
The PAX3 gene encodes a member of the PAX family of transcription factors that is characterized by a highly conserved paired box motif. The PAX3 protein is a transcription factor consisting of an N-terminal DNA binding domain (containing a paired box and homeodomain) and a C-terminal transcriptional activation domain. This protein is expressed during development of skeletal muscle, central nervous system and neural crest derivatives, and regulates expression of target genes that impact on proliferation, survival, differentiation and motility in these lineages. Germline mutations of the murine Pax3 and human PAX3 genes cause deficiencies in these developmental lineages and result in the Splotch phenotype and Waardenburg syndrome, respectively. Somatic genetic rearrangements that juxtapose the PAX3 DNA binding domain to the transcriptional activation domain of other transcription factors deregulate PAX3 function and contribute to the pathogenesis of the soft tissue cancers alveolar rhabdomyosarcoma and biphenotypic sinonasal sarcoma. The wild-type PAX3 protein is also expressed in other cancers related to developmental lineages that normally express this protein and exerts phenotypic effects related to its normal developmental role.
Topics: Animals; Gene Expression; Gene Expression Regulation, Developmental; Gene Expression Regulation, Neoplastic; Humans; Mutation; PAX3 Transcription Factor; Sarcoma; Waardenburg Syndrome
PubMed: 29730428
DOI: 10.1016/j.gene.2018.04.087