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Keywords = neurocristopathies

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24 pages, 9767 KiB  
Article
Facial Bone Defects Associated with Lateral Facial Clefts Tessier Type 6, 7 and 8 in Syndromic Neurocristopathies: A Detailed Micro-CT Analysis on Historical Museum Specimens
by Jana Behunova, Helga Rehder, Anton Dobsak, Susanne G. Kircher, Lucas L. Boer, Andreas A. Mueller, Janina M. Patsch, Eduard Winter, Roelof-Jan Oostra, Eva Piehslinger and Karoline M. Reich
Biology 2025, 14(7), 872; https://doi.org/10.3390/biology14070872 - 17 Jul 2025
Viewed by 322
Abstract
Lateral facial clefts are rare and often part of more complex syndromic neurocristopathies. According to Tessier’s classification, they correspond to facial cleft numbers 6, 7 and 8. Using micro-computer tomography (micro-CT), we analyzed their underlying bone defects (resolution 50 and 55 µm/voxel) in [...] Read more.
Lateral facial clefts are rare and often part of more complex syndromic neurocristopathies. According to Tessier’s classification, they correspond to facial cleft numbers 6, 7 and 8. Using micro-computer tomography (micro-CT), we analyzed their underlying bone defects (resolution 50 and 55 µm/voxel) in the context of the known syndrome-specific genetic background. Lateral facial clefts were diagnosed in three severely affected museum specimens representing mandibulofacial dysostosis type Treacher Collins syndrome (TCS), acrofacial dysostosis syndrome of Rodriguez (AFD-Rod) and tetra-amelia syndrome (TETAMS). The TCS specimen mainly showed an absence of the zygomatic bones and most of the lateral maxilla. The AFD-Rod specimen showed an extensive defect of the lateral maxilla, zygomatic bones, and mandible. The TETAMS specimen showed almost isolated agnathia. Possible relationships are discussed between the diverse facial bone defects due to apoptosis of neural crest-derived cells, known to be associated with ribosomopathies and spliceosomopathies, such as TCS and AFD-Rod, and the more targeted bone defects due to genetic variants known to cause TETAMS. Full article
(This article belongs to the Section Neuroscience)
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27 pages, 23298 KiB  
Article
Keratin 8/18a.1 Expression Influences Embryonic Neural Crest Cell Dynamics and Contributes to Postnatal Corneal Regeneration in Zebrafish
by Antionette L. Williams and Brenda L. Bohnsack
Cells 2024, 13(17), 1473; https://doi.org/10.3390/cells13171473 - 2 Sep 2024
Cited by 1 | Viewed by 1701
Abstract
A complete understanding of neural crest cell mechanodynamics during ocular development will provide insight into postnatal neural crest cell contributions to ophthalmic abnormalities in adult tissues and inform regenerative strategies toward injury repair. Herein, single-cell RNA sequencing in zebrafish during early eye development [...] Read more.
A complete understanding of neural crest cell mechanodynamics during ocular development will provide insight into postnatal neural crest cell contributions to ophthalmic abnormalities in adult tissues and inform regenerative strategies toward injury repair. Herein, single-cell RNA sequencing in zebrafish during early eye development revealed keratin intermediate filament genes krt8 and krt18a.1 as additional factors expressed during anterior segment development. In situ hybridization and immunofluorescence microscopy confirmed krt8 and krt18a.1 expression in the early neural plate border and migrating cranial neural crest cells. Morpholino oligonucleotide (MO)-mediated knockdown of K8 and K18a.1 markedly disrupted the migration of neural crest cell subpopulations and decreased neural crest cell marker gene expression in the craniofacial region and eye at 48 h postfertilization (hpf), resulting in severe phenotypic defects reminiscent of neurocristopathies. Interestingly, the expression of K18a.1, but not K8, is regulated by retinoic acid (RA) during early-stage development. Further, both keratin proteins were detected during postnatal corneal regeneration in adult zebrafish. Altogether, we demonstrated that both K8 and K18a.1 contribute to the early development and postnatal repair of neural crest cell-derived ocular tissues. Full article
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35 pages, 1273 KiB  
Review
Clinical and Genetic Correlation in Neurocristopathies: Bridging a Precision Medicine Gap
by Despoina Chatzi, Stella Aikaterini Kyriakoudi, Iasonas Dermitzakis, Maria Eleni Manthou, Soultana Meditskou and Paschalis Theotokis
J. Clin. Med. 2024, 13(8), 2223; https://doi.org/10.3390/jcm13082223 - 11 Apr 2024
Cited by 6 | Viewed by 3310
Abstract
Neurocristopathies (NCPs) encompass a spectrum of disorders arising from issues during the formation and migration of neural crest cells (NCCs). NCCs undergo epithelial–mesenchymal transition (EMT) and upon key developmental gene deregulation, fetuses and neonates are prone to exhibit diverse manifestations depending on the [...] Read more.
Neurocristopathies (NCPs) encompass a spectrum of disorders arising from issues during the formation and migration of neural crest cells (NCCs). NCCs undergo epithelial–mesenchymal transition (EMT) and upon key developmental gene deregulation, fetuses and neonates are prone to exhibit diverse manifestations depending on the affected area. These conditions are generally rare and often have a genetic basis, with many following Mendelian inheritance patterns, thus making them perfect candidates for precision medicine. Examples include cranial NCPs, like Goldenhar syndrome and Axenfeld–Rieger syndrome; cardiac–vagal NCPs, such as DiGeorge syndrome; truncal NCPs, like congenital central hypoventilation syndrome and Waardenburg syndrome; and enteric NCPs, such as Hirschsprung disease. Additionally, NCCs’ migratory and differentiating nature makes their derivatives prone to tumors, with various cancer types categorized based on their NCC origin. Representative examples include schwannomas and pheochromocytomas. This review summarizes current knowledge of diseases arising from defects in NCCs’ specification and highlights the potential of precision medicine to remedy a clinical phenotype by targeting the genotype, particularly important given that those affected are primarily infants and young children. Full article
(This article belongs to the Special Issue Review Special Issue Series: Current Advances in Clinical Neurology)
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17 pages, 1753 KiB  
Article
Waardenburg Syndrome: The Contribution of Next-Generation Sequencing to the Identification of Novel Causative Variants
by William Bertani-Torres, Karina Lezirovitz, Danillo Alencar-Coutinho, Eliete Pardono, Silvia Souza da Costa, Larissa do Nascimento Antunes, Judite de Oliveira, Paulo Alberto Otto, Véronique Pingault and Regina Célia Mingroni-Netto
Audiol. Res. 2024, 14(1), 9-25; https://doi.org/10.3390/audiolres14010002 - 21 Dec 2023
Cited by 4 | Viewed by 2849
Abstract
Waardenburg syndrome (WS) is characterized by hearing loss and pigmentary abnormalities of the eyes, hair, and skin. The condition is genetically heterogeneous, and is classified into four clinical types differentiated by the presence of dystopia canthorum in type 1 and its absence in [...] Read more.
Waardenburg syndrome (WS) is characterized by hearing loss and pigmentary abnormalities of the eyes, hair, and skin. The condition is genetically heterogeneous, and is classified into four clinical types differentiated by the presence of dystopia canthorum in type 1 and its absence in type 2. Additionally, limb musculoskeletal abnormalities and Hirschsprung disease differentiate types 3 and 4, respectively. Genes PAX3, MITF, SOX10, KITLG, EDNRB, and EDN3 are already known to be associated with WS. In WS, a certain degree of molecularly undetected patients remains, especially in type 2. This study aims to pinpoint causative variants using different NGS approaches in a cohort of 26 Brazilian probands with possible/probable diagnosis of WS1 (8) or WS2 (18). DNA from the patients was first analyzed by exome sequencing. Seven of these families were submitted to trio analysis. For inconclusive cases, we applied a targeted NGS panel targeting WS/neurocristopathies genes. Causative variants were detected in 20 of the 26 probands analyzed, these being five in PAX3, eight in MITF, two in SOX10, four in EDNRB, and one in ACTG1 (type 2 Baraitser-Winter syndrome, BWS2). In conclusion, in our cohort of patients, the detection rate of the causative variant was 77%, confirming the superior detection power of NGS in genetically heterogeneous diseases. Full article
(This article belongs to the Special Issue Genetics of Hearing Loss—Volume II)
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20 pages, 6102 KiB  
Review
The Emerging Roles of the Cephalic Neural Crest in Brain Development and Developmental Encephalopathies
by Emmanuel Bruet, Diego Amarante-Silva, Tatiana Gorojankina and Sophie Creuzet
Int. J. Mol. Sci. 2023, 24(12), 9844; https://doi.org/10.3390/ijms24129844 - 7 Jun 2023
Cited by 7 | Viewed by 4840
Abstract
The neural crest, a unique cell population originating from the primitive neural field, has a multi-systemic and structural contribution to vertebrate development. At the cephalic level, the neural crest generates most of the skeletal tissues encasing the developing forebrain and provides the prosencephalon [...] Read more.
The neural crest, a unique cell population originating from the primitive neural field, has a multi-systemic and structural contribution to vertebrate development. At the cephalic level, the neural crest generates most of the skeletal tissues encasing the developing forebrain and provides the prosencephalon with functional vasculature and meninges. Over the last decade, we have demonstrated that the cephalic neural crest (CNC) exerts an autonomous and prominent control on the development of the forebrain and sense organs. The present paper reviews the primary mechanisms by which CNC can orchestrate vertebrate encephalization. Demonstrating the role of the CNC as an exogenous source of patterning for the forebrain provides a novel conceptual framework with profound implications for understanding neurodevelopment. From a biomedical standpoint, these data suggest that the spectrum of neurocristopathies is broader than expected and that some neurological disorders may stem from CNC dysfunctions. Full article
(This article belongs to the Special Issue Neural Crest Development in Health and Disease (Volume 2))
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12 pages, 3547 KiB  
Case Report
Multifocal Neuroblastoma and Central Hypoventilation in An Infant with Germline ALK F1174I Mutation
by Anna Djos, Diana Treis, Susanne Fransson, Lena Gordon Murkes, Sandra Wessman, Jurate Ásmundsson, Agneta Markström, Per Kogner and Tommy Martinsson
Diagnostics 2022, 12(9), 2260; https://doi.org/10.3390/diagnostics12092260 - 19 Sep 2022
Viewed by 2299
Abstract
A preterm infant with central hypoventilation was diagnosed with multifocal neuroblastoma. Congenital anomalies of the autonomic nervous system in association with neuroblastoma are commonly associated with germline mutations in PHOX2B. Further, the ALK gene is frequently mutated in both familial and sporadic [...] Read more.
A preterm infant with central hypoventilation was diagnosed with multifocal neuroblastoma. Congenital anomalies of the autonomic nervous system in association with neuroblastoma are commonly associated with germline mutations in PHOX2B. Further, the ALK gene is frequently mutated in both familial and sporadic neuroblastoma. Sanger sequencing of ALK and PHOX2B, SNP microarray of three tumor samples and whole genome sequencing of tumor and blood were performed. Genetic testing revealed a germline ALK F1174I mutation that was present in all tumor samples as well as in normal tissue samples from the patient. Neither of the patient’s parents presented the ALK variant. Array profiling of the three tumor samples showed that two of them had only numerical aberrations, whereas one sample displayed segmental alterations, including a gain at chromosome 2p, resulting in two copies of the ALK-mutated allele. Whole genome sequencing confirmed the presence of the ALK variant and did not detect any aberrations in the coding or promotor region of PHOX2B. This study is to our knowledge the first to report a de novoALK F1174I germline mutation. This may not only predispose to congenital multifocal neuroblastoma but may also contribute to the respiratory dysfunction seen in this patient. Full article
(This article belongs to the Special Issue Genetic Diagnosis of Pediatric Diseases)
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18 pages, 4598 KiB  
Article
Craniofacial Defects in Embryos with Homozygous Deletion of Eftud2 in Their Neural Crest Cells Are Not Rescued by Trp53 Deletion
by Marie-Claude Beauchamp, Alexia Boucher, Yanchen Dong, Rachel Aber and Loydie A. Jerome-Majewska
Int. J. Mol. Sci. 2022, 23(16), 9033; https://doi.org/10.3390/ijms23169033 - 12 Aug 2022
Cited by 10 | Viewed by 2431
Abstract
Embryos with homozygous mutation of Eftud2 in their neural crest cells (Eftud2ncc−/−) have brain and craniofacial malformations, hyperactivation of the P53-pathway and die before birth. Treatment of Eftud2ncc−/− embryos with pifithrin-α, a P53-inhibitor, partly improved brain and craniofacial development. [...] Read more.
Embryos with homozygous mutation of Eftud2 in their neural crest cells (Eftud2ncc−/−) have brain and craniofacial malformations, hyperactivation of the P53-pathway and die before birth. Treatment of Eftud2ncc−/− embryos with pifithrin-α, a P53-inhibitor, partly improved brain and craniofacial development. To uncover if craniofacial malformations and death were indeed due to P53 hyperactivation we generated embryos with homozygous loss of function mutations in both Eftud2 and Trp53 in the neural crest cells. We evaluated the molecular mechanism underlying craniofacial development in pifithrin-α-treated embryos and in Eftud2; Trp53 double homozygous (Eftud2ncc−/−; Trp53ncc−/−) mutant embryos. Eftud2ncc−/− embryos that were treated with pifithrin-α or homozygous mutant for Trp53 in their neural crest cells showed reduced apoptosis in their neural tube and reduced P53-target activity. Furthermore, although the number of SOX10 positive cranial neural crest cells was increased in embryonic day (E) 9.0 Eftud2ncc−/−; Trp53ncc−/− embryos compared to Eftud2ncc−/− mutants, brain and craniofacial development, and survival were not improved in double mutant embryos. Furthermore, mis-splicing of both P53-regulated transcripts, Mdm2 and Foxm1, and a P53-independent transcript, Synj2bp, was increased in the head of Eftud2ncc−/−; Trp53ncc−/− embryos. While levels of Zmat3, a P53- regulated splicing factor, was similar to those of wild-type. Altogether, our data indicate that both P53-regulated and P53-independent pathways contribute to craniofacial malformations and death of Eftud2ncc−/− embryos. Full article
(This article belongs to the Special Issue Neural Crest Development in Health and Disease)
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17 pages, 2298 KiB  
Review
Roles of Enteric Neural Stem Cell Niche and Enteric Nervous System Development in Hirschsprung Disease
by Yue Ji, Paul Kwong-Hang Tam and Clara Sze-Man Tang
Int. J. Mol. Sci. 2021, 22(18), 9659; https://doi.org/10.3390/ijms22189659 - 7 Sep 2021
Cited by 28 | Viewed by 5345
Abstract
The development of the enteric nervous system (ENS) is highly modulated by the synchronized interaction between the enteric neural crest cells (ENCCs) and the neural stem cell niche comprising the gut microenvironment. Genetic defects dysregulating the cellular behaviour(s) of the ENCCs result in [...] Read more.
The development of the enteric nervous system (ENS) is highly modulated by the synchronized interaction between the enteric neural crest cells (ENCCs) and the neural stem cell niche comprising the gut microenvironment. Genetic defects dysregulating the cellular behaviour(s) of the ENCCs result in incomplete innervation and hence ENS dysfunction. Hirschsprung disease (HSCR) is a rare complex neurocristopathy in which the enteric neural crest-derived cells fail to colonize the distal colon. In addition to ENS defects, increasing evidence suggests that HSCR patients may have intrinsic defects in the niche impairing the extracellular matrix (ECM)-cell interaction and/or dysregulating the cellular niche factors necessary for controlling stem cell behaviour. The niche defects in patients may compromise the regenerative capacity of the stem cell-based therapy and advocate for drug- and niche-based therapies as complementary therapeutic strategies to alleviate/enhance niche-cell interaction. Here, we provide a summary of the current understandings of the role of the enteric neural stem cell niche in modulating the development of the ENS and in the pathogenesis of HSCR. Deciphering the contribution of the niche to HSCR may provide important implications to the development of regenerative medicine for HSCR. Full article
(This article belongs to the Special Issue Neural Crest Development in Health and Disease)
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14 pages, 2602 KiB  
Article
ChIP-Seq-Based Approach in Mouse Enteric Precursor Cells Reveals New Potential Genes with a Role in Enteric Nervous System Development and Hirschsprung Disease
by Leticia Villalba-Benito, Ana Torroglosa, Berta Luzón-Toro, Raquel María Fernández, María José Moya-Jiménez, Guillermo Antiñolo and Salud Borrego
Int. J. Mol. Sci. 2020, 21(23), 9061; https://doi.org/10.3390/ijms21239061 - 28 Nov 2020
Cited by 5 | Viewed by 2713
Abstract
Hirschsprung disease (HSCR) is a neurocristopathy characterized by intestinal aganglionosis which is attributed to a failure in neural crest cell (NCC) development during the embryonic stage. The colonization of the intestine by NCCs is a process finely controlled by a wide and complex [...] Read more.
Hirschsprung disease (HSCR) is a neurocristopathy characterized by intestinal aganglionosis which is attributed to a failure in neural crest cell (NCC) development during the embryonic stage. The colonization of the intestine by NCCs is a process finely controlled by a wide and complex gene regulatory system. Several genes have been associated with HSCR, but many aspects still remain poorly understood. The present study is focused on deciphering the PAX6 interaction network during enteric nervous system (ENS) formation. A combined experimental and computational approach was performed to identify PAX6 direct targets, as well as gene networks shared among such targets as potential susceptibility factors for HSCR. As a result, genes related to PAX6 either directly (RABGGTB and BRD3) or indirectly (TGFB1, HRAS, and GRB2) were identified as putative genes associated with HSCR. Interestingly, GRB2 is involved in the RET/GDNF/GFRA1 signaling pathway, one of the main pathways implicated in the disease. Our findings represent a new contribution to advance in the knowledge of the genetic basis of HSCR. The investigation of the role of these genes could help to elucidate their implication in HSCR onset. Full article
(This article belongs to the Special Issue Biomarkers in Rare Diseases)
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13 pages, 1585 KiB  
Review
Hirschsprung’s Disease—Recent Understanding of Embryonic Aspects, Etiopathogenesis and Future Treatment Avenues
by Martin Klein and Ivan Varga
Medicina 2020, 56(11), 611; https://doi.org/10.3390/medicina56110611 - 13 Nov 2020
Cited by 37 | Viewed by 8950
Abstract
Hirschsprung’s disease is a neurocristopathy, caused by defective migration, proliferation, differentiation and survival of neural crest cells, leading to gut aganglionosis. It usually manifests rapidly after birth, affecting 1 in 5000 live births around the globe. In recent decades, there has been a [...] Read more.
Hirschsprung’s disease is a neurocristopathy, caused by defective migration, proliferation, differentiation and survival of neural crest cells, leading to gut aganglionosis. It usually manifests rapidly after birth, affecting 1 in 5000 live births around the globe. In recent decades, there has been a significant improvement in the understanding of its genetics and the association with other congenital anomalies, which share the pathomechanism of improper development of the neural crest. Apart from that, several cell populations which do not originate from the neural crest, but contribute to the development of Hirschsprung’s disease, have also been described, namely mast cells and interstitial cells of Cajal. From the diagnostic perspective, researchers also focused on “Variants of Hirschsprung’s disease”, which can mimic the clinical signs of the disease, but are in fact different entities, with distinct prognosis and treatment approaches. The treatment of Hirschsprung’s disease is usually surgical resection of the aganglionic part of the intestine, however, as many as 30–50% of patients experience persisting symptoms. Considering this fact, this review article also outlines future hopes and perspectives in Hirschsprung’s disease management, which has the potential to benefit from the advancements in the fields of cell-based therapy and tissue engineering. Full article
(This article belongs to the Special Issue Variational Anatomy and Developmental Anomalies in Clinical Practice)
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13 pages, 747 KiB  
Communication
Identification of New Potential LncRNA Biomarkers in Hirschsprung Disease
by Ana Torroglosa, Leticia Villalba-Benito, Raquel María Fernández, Berta Luzón-Toro, María José Moya-Jiménez, Guillermo Antiñolo and Salud Borrego
Int. J. Mol. Sci. 2020, 21(15), 5534; https://doi.org/10.3390/ijms21155534 - 2 Aug 2020
Cited by 12 | Viewed by 3714
Abstract
Hirschsprung disease (HSCR) is a neurocristopathy defined by intestinal aganglionosis due to alterations during the development of the Enteric Nervous System (ENS). A wide spectrum of molecules involved in different signaling pathways and mechanisms have been described in HSCR onset. Among them, epigenetic [...] Read more.
Hirschsprung disease (HSCR) is a neurocristopathy defined by intestinal aganglionosis due to alterations during the development of the Enteric Nervous System (ENS). A wide spectrum of molecules involved in different signaling pathways and mechanisms have been described in HSCR onset. Among them, epigenetic mechanisms are gaining increasing relevance. In an effort to better understand the epigenetic basis of HSCR, we have performed an analysis for the identification of long non-coding RNAs (lncRNAs) by qRT-PCR in enteric precursor cells (EPCs) from controls and HSCR patients. We aimed to test the presence of a set lncRNAs among 84 lncRNAs in human EPCs, which were previously related with crucial cellular processes for ENS development, as well as to identify the possible differences between HSCR patients and controls. As a result, we have determined a set of lncRNAs with positive expression in human EPCs that were screened for mutations using the exome data from our cohort of HSCR patients to identify possible variants related to this pathology. Interestingly, we identified three lncRNAs with different levels of their transcripts (SOCS2-AS, MEG3 and NEAT1) between HSCR patients and controls. We propose such lncRNAs as possible regulatory elements implicated in the onset of HSCR as well as potential biomarkers of this pathology. Full article
(This article belongs to the Special Issue Biomarkers in Rare Diseases)
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18 pages, 1097 KiB  
Article
Autosomal Dominantly Inherited GREB1L Variants in Individuals with Profound Sensorineural Hearing Impairment
by Isabelle Schrauwen, Khurram Liaqat, Isabelle Schatteman, Thashi Bharadwaj, Abdul Nasir, Anushree Acharya, Wasim Ahmad, Guy Van Camp and Suzanne M. Leal
Genes 2020, 11(6), 687; https://doi.org/10.3390/genes11060687 - 23 Jun 2020
Cited by 27 | Viewed by 5457
Abstract
Congenital hearing impairment is a sensory disorder that is genetically highly heterogeneous. By performing exome sequencing in two families with congenital nonsyndromic profound sensorineural hearing loss (SNHL), we identified autosomal dominantly inherited missense variants [p.(Asn283Ser); p.(Thr116Ile)] in GREB1L, a neural crest regulatory [...] Read more.
Congenital hearing impairment is a sensory disorder that is genetically highly heterogeneous. By performing exome sequencing in two families with congenital nonsyndromic profound sensorineural hearing loss (SNHL), we identified autosomal dominantly inherited missense variants [p.(Asn283Ser); p.(Thr116Ile)] in GREB1L, a neural crest regulatory molecule. The p.(Thr116Ile) variant was also associated with bilateral cochlear aplasia and cochlear nerve aplasia upon temporal bone imaging, an ultra-rare phenotype previously seen in patients with de novo GREB1L variants. An important role of GREB1L in normal ear development has also been demonstrated by greb1l−/− zebrafish, which show an abnormal sensory epithelia innervation. Last, we performed a review of all disease-associated variation described in GREB1L, as it has also been implicated in renal, bladder and genital malformations. We show that the spectrum of features associated with GREB1L is broad, variable and with a high level of reduced penetrance, which is typically characteristic of neurocristopathies. So far, seven GREB1L variants (14%) have been associated with ear-related abnormalities. In conclusion, these results show that autosomal dominantly inherited variants in GREB1L cause profound SNHL. Furthermore, we provide an overview of the phenotypic spectrum associated with GREB1L variants and strengthen the evidence of the involvement of GREB1L in human hearing. Full article
(This article belongs to the Special Issue Genetics of Hearing Impairment)
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10 pages, 1065 KiB  
Case Report
Congenital Sensorineural Hearing Loss and Inborn Pigmentary Disorders: First Report of Multilocus Syndrome in Piebaldism
by Laura Cristina Gironi, Enrico Colombo, Alfredo Brusco, Enrico Grosso, Valeria Giorgia Naretto, Andrea Guala, Eleonora Di Gregorio, Andrea Zonta, Francesca Zottarelli, Barbara Pasini and Paola Savoia
Medicina 2019, 55(7), 345; https://doi.org/10.3390/medicina55070345 - 7 Jul 2019
Cited by 4 | Viewed by 3186
Abstract
Congenital sensorineural hearing loss may occur in association with inborn pigmentary defects of the iris, hair, and skin. These conditions, named auditory-pigmentary disorders (APDs), represent extremely heterogeneous hereditary diseases, including Waardenburg syndromes, oculocutaneous albinism, Tietz syndrome, and piebaldism. APDs are part of the [...] Read more.
Congenital sensorineural hearing loss may occur in association with inborn pigmentary defects of the iris, hair, and skin. These conditions, named auditory-pigmentary disorders (APDs), represent extremely heterogeneous hereditary diseases, including Waardenburg syndromes, oculocutaneous albinism, Tietz syndrome, and piebaldism. APDs are part of the neurocristopathies, a group of congenital multisystem disorders caused by an altered development of the neural crest cells, multipotent progenitors of a wide variety of different lineages, including those differentiating into peripheral nervous system glial cells and melanocytes. We report on clinical and genetic findings of two monozygotic twins from a large Albanian family who showed a complex phenotype featured by sensorineural congenital deafness, severe neuropsychiatric impairment, and inborn pigmentary defects of hair and skin. The genetic analyzes identified, in both probands, an unreported co-occurrence of a new heterozygous germline pathogenic variant (c.2484 + 5G > T splicing mutation) in the KIT gene, consistent with the diagnosis of piebaldism, and a heterozygous deletion at chromosome 15q13.3, responsible for the neuropsychiatric impairment. This case represents the first worldwide report of dual locus inherited syndrome in piebald patients affected by a complex auditory-pigmentary multisystem phenotype. Here we also synthesize the clinical and genetic findings of all known neurocristopathies characterized by a hypopigmentary congenital disorder. Full article
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13 pages, 749 KiB  
Review
Epigenetic Mechanisms in Hirschsprung Disease
by Ana Torroglosa, Leticia Villalba-Benito, Berta Luzón-Toro, Raquel María Fernández, Guillermo Antiñolo and Salud Borrego
Int. J. Mol. Sci. 2019, 20(13), 3123; https://doi.org/10.3390/ijms20133123 - 26 Jun 2019
Cited by 29 | Viewed by 6127
Abstract
Hirschsprung disease (HSCR, OMIM 142623) is due to a failure of enteric precursor cells derived from neural crest (EPCs) to proliferate, migrate, survive or differentiate during Enteric Nervous System (ENS) formation. This is a complex process which requires a strict regulation that results [...] Read more.
Hirschsprung disease (HSCR, OMIM 142623) is due to a failure of enteric precursor cells derived from neural crest (EPCs) to proliferate, migrate, survive or differentiate during Enteric Nervous System (ENS) formation. This is a complex process which requires a strict regulation that results in an ENS specific gene expression pattern. Alterations at this level lead to the onset of neurocristopathies such as HSCR. Gene expression is regulated by different mechanisms, such as DNA modifications (at the epigenetic level), transcriptional mechanisms (transcription factors, silencers, enhancers and repressors), postranscriptional mechanisms (3′UTR and ncRNA) and regulation of translation. All these mechanisms are finally implicated in cell signaling to determine the migration, proliferation, differentiation and survival processes for correct ENS development. In this review, we have performed an overview on the role of epigenetic mechanisms at transcriptional and posttranscriptional levels on these cellular events in neural crest cells (NCCs), ENS development, as well as in HSCR. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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