-
Current Osteoporosis Reports Feb 2016The SOXC group of transcription factors, composed of SOX4, SOX11, and SOX12, has evolved to fulfill key functions in cell fate determination. Expressed in many types of... (Review)
Review
The SOXC group of transcription factors, composed of SOX4, SOX11, and SOX12, has evolved to fulfill key functions in cell fate determination. Expressed in many types of progenitor/stem cells, including skeletal progenitors, SOXC proteins potentiate pathways critical for cell survival and differentiation. As skeletogenesis unfolds, SOXC proteins ensure cartilage primordia delineation by amplifying canonical WNT signaling and antagonizing the chondrogenic action of SOX9 in perichondrium and presumptive articular joint cells. They then ensure skeletal elongation by inducing growth plate formation via enabling non-canonical WNT signaling. Human studies have associated SOX4 with bone mineral density and fracture risk in osteoporotic patients, and SOX11 with Coffin-Siris, a syndrome that includes skeletal dysmorphism. Meanwhile, in vitro and mouse studies have suggested important cell-autonomous roles for SOXC proteins in osteoblastogenesis. We here review current knowledge and gaps in understanding of SOXC protein functions, with an emphasis on the skeleton and possible links to osteoporosis.
Topics: Abnormalities, Multiple; Animals; Bone Density; Bone Development; Cell Differentiation; Chondrogenesis; Face; Hand Deformities, Congenital; Humans; Intellectual Disability; Mice; Micrognathism; Neck; Osteoblasts; Osteoporotic Fractures; SOX9 Transcription Factor; SOXC Transcription Factors; Stem Cells; Wnt Signaling Pathway
PubMed: 26830765
DOI: 10.1007/s11914-016-0296-1 -
Biochemical Society Transactions Dec 2016Defects in the development of the mandible can lead to micrognathia, or small jaw, which manifests in ciliopathic conditions, such as orofaciodigital syndrome,... (Review)
Review
Defects in the development of the mandible can lead to micrognathia, or small jaw, which manifests in ciliopathic conditions, such as orofaciodigital syndrome, Meckel-Gruber syndrome, and Bardet-Biedl syndrome. Although micrognathia occurs frequently in human and mouse ciliopathies, it has been difficult to pinpoint the underlying cellular causes. In this mini-review, we shed light on the tissue-specific contributions to ciliary dysfunction in the development of the mandible. First, we outline the steps involved in setting up the jaw primordium and subsequent steps in the outgrowth of the mandibular skeleton. We then determine the critical tissue interactions using mice carrying a conditional mutation in the cilia gene Ofd1 Our studies highlight the usefulness of the Ofd1 mouse model and illustrate long-term possibilities for understanding the cellular and biochemical events underlying micrognathia.
Topics: Animals; Cilia; Ciliopathies; Disease Models, Animal; Humans; Mandible; Mice; Micrognathism; Mutation; Proteins
PubMed: 27913686
DOI: 10.1042/BST20160241 -
Clinics in Perinatology Dec 2018Congenital causes of airway obstruction once noted at birth are now diagnosed prenatally. The adoption of ex utero intrapartum treatment has allowed for planned airway... (Review)
Review
Congenital causes of airway obstruction once noted at birth are now diagnosed prenatally. The adoption of ex utero intrapartum treatment has allowed for planned airway stabilization on placental support, dramatically decreasing the incidence of hypoxic injury or peripartum demise related to neonatal airway obstruction. Airway access is gained either through laryngoscopy, bronchoscopy, or a surgical airway. In complete airway obstruction, primary resection of the obstructing lesion may be performed before completion of delivery. This article reviews the current and emerging methods of fetal evaluation, indications for ex utero intrapartum treatment, and provides a detailed description of the procedure and necessary personnel.
Topics: Airway Management; Airway Obstruction; Female; Fetal Diseases; Humans; Magnetic Resonance Imaging; Male; Micrognathism; Pregnancy; Pregnancy Outcome; Prenatal Care; Plastic Surgery Procedures; Respiratory System Abnormalities; Risk Assessment; Treatment Outcome; Ultrasonography, Prenatal
PubMed: 30396408
DOI: 10.1016/j.clp.2018.07.003 -
Otolaryngologic Clinics of North America Aug 2024Oral causes of dysphagia in infancy may involve the lips, the tongue, or the palate. Whereas ankyloglossia is commonly diagnosed in infants with dysphagia, assessment of... (Review)
Review
Oral causes of dysphagia in infancy may involve the lips, the tongue, or the palate. Whereas ankyloglossia is commonly diagnosed in infants with dysphagia, assessment of the need for surgical intervention may be less straightforward. Tongue size (macroglossia) may be associated with dysphagia as it may cause limitation of movement of the food or milk bolus by the lips or cheeks. Congenital conditions such as cleft lip and palate, micrognathia, or craniofacial microsomia may also be associated with dysphagia. Diagnosis and treatment of these conditions can be improved with the engagement of lactation and feeding experts as well as multidisciplinary craniofacial teams.
Topics: Humans; Deglutition Disorders; Infant; Tongue; Child; Ankyloglossia; Cleft Palate; Cleft Lip; Lip; Mouth Abnormalities; Micrognathism
PubMed: 38503668
DOI: 10.1016/j.otc.2024.02.012 -
The Journal of Craniofacial Surgery Mar 2018The Pierre Robin sequence (PRS) has been defined as the presence of micrognathia, glossoptosis, and respiratory obstruction in the neonatal period. Since its original... (Review)
Review
BACKGROUND
The Pierre Robin sequence (PRS) has been defined as the presence of micrognathia, glossoptosis, and respiratory obstruction in the neonatal period. Since its original description, different therapeutic approaches have been proposed obtaining different success rates, but there is no consensus about its management.
METHODS
A literature review was conducted in PubMed, Embase, and Cochrane databases, for the period of January,1985 to November, 2016. A number of 23 articles resulting from clinical studies, discussing diagnostic tests or therapeutic approaches, and directly or indirectly comparing diagnostic or treatment modalities were selected and assessed using the GRADE methodology.
RESULTS
After reviewing and analyzing the selected articles, an evidence-based algorithm for diagnosis and integral management of PRS patients was designed.
CONCLUSION
Based on the anatomical principles and natural evolution of PRS, the clinical scenario must be evaluated thoroughly as a dynamic event to develop a management sequence that minimizes morbidity and mortality and accelerates patients' reinsertion to normal life.
Topics: Airway Obstruction; Glossoptosis; Humans; Micrognathism; Pierre Robin Syndrome
PubMed: 29215441
DOI: 10.1097/SCS.0000000000004178 -
European Journal of Human Genetics :... Aug 2023High-throughput sequencing has become a standard first-tier approach for both diagnostics and research-based genetic testing. Consequently, this hypothesis-free... (Review)
Review
High-throughput sequencing has become a standard first-tier approach for both diagnostics and research-based genetic testing. Consequently, this hypothesis-free testing manner has revealed the true breadth of clinical features for many established genetic disorders, including Meier-Gorlin syndrome (MGORS). Previously known as ear-patella short stature syndrome, MGORS is characterized by growth delay, microtia, and patella hypo/aplasia, as well as genital abnormalities, and breast agenesis in females. Following the initial identification of genetic causes in 2011, a total of 13 genes have been identified to date associated with MGORS. In this review, we summarise the genetic and clinical findings of each gene associated with MGORS and highlight molecular insights that have been made through studying patient variants. We note interesting observations arising across this group of genes as the number of patients has increased, such as the unusually high number of synonymous variants affecting splicing in CDC45 and a subgroup of genes that also cause craniosynostosis. We focus on the complicated molecular genetics for DONSON, where we examine potential genotype-phenotype patterns using the first 3D structural model of DONSON. The canonical role of all proteins associated with MGORS are involved in different stages of DNA replication and in addition to summarising how patient variants impact on this process, we discuss the potential contribution of non-canonical roles of these proteins to the pathophysiology of MGORS.
Topics: Female; Humans; Congenital Microtia; Patella; Growth Disorders; Micrognathism
PubMed: 37059840
DOI: 10.1038/s41431-023-01359-z -
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 -
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