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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 -
Frontiers in Bioscience (Landmark... Jan 2017Mammalian mitochondrial DNA (mtDNA) exists in structures called nucleoids, which correspond to the configuration of nuclear DNA. Mitochondrial transcription factor A... (Review)
Review
Mammalian mitochondrial DNA (mtDNA) exists in structures called nucleoids, which correspond to the configuration of nuclear DNA. Mitochondrial transcription factor A (TFAM), first cloned as an mtDNA transcription factor, is critical for packaging and maintaining mtDNA. To investigate functional aspects of TFAM, we identified many RNA-binding proteins as candidate TFAM interactors, including ERAL1 and p32. In this review, we first describe the functions of TFAM, replication proteins such as polymerase gamma and Twinkle, and mitochondrial RNA binding proteins. We describe the role of mitochondrial nucleic acid binding proteins within the mitochondrial matrix and two oxidative phosphorylation-related proteins within the mitochondrial intermembrane space. We then discuss how mitochondrial dysfunction is related to several diseases, including mitochondrial respiratory disease, Miller syndrome and cancer. We also describe p32 knockout mice, which are embryonic lethal and exhibit respiratory chain defects. Miller syndrome is a recessive disorder characterized by postaxial acrofacial dysostosis and caused by a mutation in . Finally, we explain that p32 and mitochondrial creatine kinase may be novel markers for the progression of prostate cancer.
Topics: Abnormalities, Multiple; Animals; Carrier Proteins; DNA Helicases; DNA Polymerase gamma; DNA, Mitochondrial; DNA-Binding Proteins; GTP-Binding Proteins; Humans; Limb Deformities, Congenital; Mandibulofacial Dysostosis; Mice; Micrognathism; Mitochondrial Diseases; Mitochondrial Proteins; Mutation; Neoplasm Proteins; Neoplasms; RNA-Binding Proteins; Ribonuclease P; Transcription Factors
PubMed: 27814609
DOI: 10.2741/4479 -
European Journal of Dentistry Oct 2021Previous studies showed that noggin gene () sequence alterations, as well as epigenetic factors, could influence mandibular development. The aim of this study was to...
OBJECTIVES
Previous studies showed that noggin gene () sequence alterations, as well as epigenetic factors, could influence mandibular development. The aim of this study was to analyze clinical characteristics, gene sequences, and promoter methylation sites in patients with mandibular micrognathism.
MATERIALS AND METHODS
A total of 35 individuals of five Colombian families were subject to clinical and cephalometric analysis for mandibular micrognathism. One nonaffected individual of each family was included as a control. DNA was isolated from whole blood sample from all individuals by salting out method. Nine gene fragments were amplified by polymerase chain reaction (PCR) and sequenced. Identification of CpG islands for methylation analysis at the gene promoter was performed by MSP-PCR kit (Qiagen R).
STATISTICAL ANALYSIS
A descriptive statistical analysis was carried out evaluating the presence or absence of genetics variants and the methylation sites in the NOG gene.
RESULTS
sequence results of affected individuals with mandibular micrognathism for one of the families studied demonstrated that they were heterozygous for 672 C/A (new mutation). For a second family, individuals were heterozygous for 567 G/C (single nucleotide polymorphism [SNP] RS116716909). For DNA analyzed from all patients studied, no methylations were observed at the gene promoter region.
CONCLUSION
Our results suggested that 672 C/A and 567 G/C variants could be involved in the presence of mandibular micrognathism. Moreover, lack of methylation sites at the gene promoter region of all individuals studied suggests possibly other epigenetic factors could modulate mandibular growth. The search of genetic variants related with mandibular micrognathism will allow to predict in an integral way the development patterns of the patients and therefore establish a better clinical treatment.
PubMed: 34592770
DOI: 10.1055/s-0041-1726162 -
Genetics in Medicine : Official Journal... Jan 2023Craniofacial microsomia (CFM) represents a spectrum of craniofacial malformations, ranging from isolated microtia with or without aural atresia to underdevelopment of...
PURPOSE
Craniofacial microsomia (CFM) represents a spectrum of craniofacial malformations, ranging from isolated microtia with or without aural atresia to underdevelopment of the mandible, maxilla, orbit, facial soft tissue, and/or facial nerve. The genetic causes of CFM remain largely unknown.
METHODS
We performed genome sequencing and linkage analysis in patients and families with microtia and CFM of unknown genetic etiology. The functional consequences of damaging missense variants were evaluated through expression of wild-type and mutant proteins in vitro.
RESULTS
We studied a 5-generation kindred with microtia, identifying a missense variant in FOXI3 (p.Arg236Trp) as the cause of disease (logarithm of the odds = 3.33). We subsequently identified 6 individuals from 3 additional kindreds with microtia-CFM spectrum phenotypes harboring damaging variants in FOXI3, a regulator of ectodermal and neural crest development. Missense variants in the nuclear localization sequence were identified in cases with isolated microtia with aural atresia and found to affect subcellular localization of FOXI3. Loss of function variants were found in patients with microtia and mandibular hypoplasia (CFM), suggesting dosage sensitivity of FOXI3.
CONCLUSION
Damaging variants in FOXI3 are the second most frequent genetic cause of CFM, causing 1% of all cases, including 13% of familial cases in our cohort.
Topics: Humans; Goldenhar Syndrome; Congenital Microtia; Ear; Face; Micrognathism
PubMed: 36260083
DOI: 10.1016/j.gim.2022.09.005 -
Genetics in Medicine : Official Journal... Aug 2022Genome-wide sequencing is increasingly being performed during pregnancy to identify the genetic cause of congenital anomalies. The interpretation of prenatally...
PURPOSE
Genome-wide sequencing is increasingly being performed during pregnancy to identify the genetic cause of congenital anomalies. The interpretation of prenatally identified variants can be challenging and is hampered by our often limited knowledge of prenatal phenotypes. To better delineate the prenatal phenotype of Coffin-Siris syndrome (CSS), we collected clinical data from patients with a prenatal phenotype and a pathogenic variant in one of the CSS-associated genes.
METHODS
Clinical data was collected through an extensive web-based survey.
RESULTS
We included 44 patients with a variant in a CSS-associated gene and a prenatal phenotype; 9 of these patients have been reported before. Prenatal anomalies that were frequently observed in our cohort include hydrocephalus, agenesis of the corpus callosum, hypoplastic left heart syndrome, persistent left vena cava, diaphragmatic hernia, renal agenesis, and intrauterine growth restriction. Anal anomalies were frequently identified after birth in patients with ARID1A variants (6/14, 43%). Interestingly, pathogenic ARID1A variants were much more frequently identified in the current prenatal cohort (16/44, 36%) than in postnatal CSS cohorts (5%-9%).
CONCLUSION
Our data shed new light on the prenatal phenotype of patients with pathogenic variants in CSS genes.
Topics: Abnormalities, Multiple; Chromosomal Proteins, Non-Histone; Face; Genetic Association Studies; Hand Deformities, Congenital; Humans; Intellectual Disability; Micrognathism; Neck; Phenotype
PubMed: 35579625
DOI: 10.1016/j.gim.2022.04.010 -
Fetal Diagnosis and Therapy 2023Gómez-López-Hernández syndrome (GLHS), also known as cerebello-trigeminal-dermal dysplasia, is an extremely rare neurocutaneous disease, classically described by the...
INTRODUCTION
Gómez-López-Hernández syndrome (GLHS), also known as cerebello-trigeminal-dermal dysplasia, is an extremely rare neurocutaneous disease, classically described by the triad of rhombencephalosynapsis (RES), bilateral focal alopecia, and trigeminal anesthesia. The clinical and radiographic spectrum of GLHS is now known to be broader, including craniofacial and supratentorial anomalies, as well as neurodevelopmental issues.
CASE PRESENTATION
Here, we present a case of antenatally diagnosed GLHS with RES, hydrocephaly, and craniofacial anomalies identified on ultrasound (low-set ears with posterior rotation, hypertelorism, midface hypoplasia, micrognathia, and anteverted nares) which were confirmed by autopsy after termination of pregnancy at 23 weeks of gestation.
DISCUSSION
As no known genetic causes have been identified and the classical triad is not applicable to prenatal imaging, prenatal diagnosis of GLHS is based on neuroimaging and the identification of supporting features. In presence of an RES associated with craniofacial abnormalities in prenatal (brachycephaly, turricephaly, low-set ears, midface retrusion, micrognathia), GLHS should be considered as "possible" according to postnatal criteria.
Topics: Female; Pregnancy; Humans; Micrognathism; Cerebellum; Craniofacial Abnormalities; Alopecia; Prenatal Diagnosis
PubMed: 37062278
DOI: 10.1159/000530643 -
Genetics in Medicine : Official Journal... Jun 2022This study aimed to describe the phenotypic and molecular characteristics of ARCN1-related syndrome.
PURPOSE
This study aimed to describe the phenotypic and molecular characteristics of ARCN1-related syndrome.
METHODS
Patients with ARCN1 variants were identified, and clinician researchers were connected using GeneMatcher and physician referrals. Clinical histories were collected from each patient.
RESULTS
In total, we identified 14 cases of ARCN1-related syndrome, (9 pediatrics, and 5 fetal cases from 3 families). The clinical features these newly identified cases were compared to 6 previously reported cases for a total of 20 cases. Intrauterine growth restriction, micrognathia, and short stature were present in all patients. Other common features included prematurity (11/15, 73.3%), developmental delay (10/14, 71.4%), genitourinary malformations in males (6/8, 75%), and microcephaly (12/15, 80%). Novel features of ARCN1-related syndrome included transient liver dysfunction and specific glycosylation abnormalities during illness, giant cell hepatitis, hepatoblastoma, cataracts, and lethal skeletal manifestations. Developmental delay was seen in 73% of patients, but only 3 patients had intellectual disability, which is less common than previously reported.
CONCLUSION
ARCN1-related syndrome presents with a wide clinical spectrum ranging from a severe embryonic lethal syndrome to a mild syndrome with intrauterine growth restriction, micrognathia, and short stature without intellectual disability. Patients with ARCN1-related syndrome should be monitored for liver dysfunction during illness, cataracts, and hepatoblastoma. Additional research to further define the phenotypic spectrum and possible genotype-phenotype correlations are required.
Topics: Cataract; Child; Dwarfism; Female; Fetal Growth Retardation; Hepatoblastoma; Humans; Intellectual Disability; Liver Neoplasms; Male; Micrognathism; Phenotype; Syndrome
PubMed: 35300924
DOI: 10.1016/j.gim.2022.02.005 -
Proceedings of the Royal Society of... May 1974
Topics: Animals; Antimetabolites; Cell Differentiation; Cleft Lip; Cleft Palate; Dermoid Cyst; Eye Neoplasms; Face; Female; Glucocorticoids; Humans; Male; Mandibulofacial Dysostosis; Mice; Mice, Inbred A; Micrognathism; Morphogenesis; Phenobarbital; Pregnancy; Rats; Salicylates; Sex Factors; Stress, Mechanical; Thalidomide; Uvula
PubMed: 4835278
DOI: No ID Found -
Frontiers in Pediatrics 2023This study will list the most common comorbidities of congenital facial nerve palsy and how to detect and treat them, with special attention for ENT-problems such as...
OBJECTIVES
This study will list the most common comorbidities of congenital facial nerve palsy and how to detect and treat them, with special attention for ENT-problems such as hearing loss. Congenital facial nerve palsy is a very rare entity but in UZ Brussels hospital there was a follow-up of 16 children in the last 30 years.
METHODS
Literature review has been done, combined with thorough research of our own series of 16 children with congenital facial nerve palsy.
RESULTS
Congenital facial nerve palsy can be part of a known syndrome, most commonly Moebius syndrome, but can also appear solely. It appears often bilateral and with a severe gradation. In our series, hearing loss is frequently seen in association with congenital facial nerve palsy. Other abnormalities are dysfunction of the abducens nerve, ophthalmological problems, retro- or micrognathism and abnormalities of limbs or heart. The majority of the children in our series underwent radiological imaging (CT and/or MRI): the facial nerve but also the vestibulocochlear nerve and middle and inner ear can be evaluated.
CONCLUSION
A multidisciplinary approach of congenital facial nerve palsy is recommended as it can affect various bodily functions. Radiological imaging needs to be done to acquire additional information that can be useful for diagnostic and therapeutic purposes. Although congenital facial nerve palsy may not be treatable itself, its comorbidities can be treated and improve the quality of life of the affected child.
PubMed: 36891227
DOI: 10.3389/fped.2023.1077238 -
BMJ Case Reports Apr 2022
Topics: Humans; Maxilla; Maxillary Sinus; Micrognathism; Sjogren's Syndrome
PubMed: 35393283
DOI: 10.1136/bcr-2022-249659