-
The Journal of Neuroscience : the... Sep 2022multiple epidermal growth factor-like domains 8 (dMegf8) is a homolog of human encodes a multidomain transmembrane protein which is highly conserved across species....
multiple epidermal growth factor-like domains 8 (dMegf8) is a homolog of human encodes a multidomain transmembrane protein which is highly conserved across species. In humans, mutations cause a rare genetic disorder called Carpenter syndrome, which is frequently associated with abnormal left-right patterning, cardiac defects, and learning disabilities. is also associated with psychiatric disorders. Despite its clinical relevance, remains poorly characterized; and although it is highly conserved, studies on animal models of Megf8 are also very limited. The presence of intellectual disabilities in Carpenter syndrome patients and association of with psychiatric disorders indicate that mutations in cause underlying defects in synaptic structure and functions. In this study, we investigated the role of dMegf8 in glutamatergic synapses of the larval neuromuscular junctions (NMJ) in both males and females. We show that dMegf8 localizes to NMJ synapses and is required for proper synaptic growth. mutant larvae and adults show severe motor coordination deficits. At the NMJ, mutants show altered localization of presynaptic and postsynaptic proteins, defects in synaptic ultrastructure, and neurotransmission. Interestingly, mutants have reduced levels of the Type II BMP receptor Wishful thinking (). displays genetic interactions with () and , and in association with Dnrx and Wit plays an essential role in synapse organization. Our studies provide insights into human MEGF8 functions and potentially into mechanisms that may underlie intellectual disabilities observed in Carpenter syndrome as well as MEGF8-related synaptic structural and/or functional deficits in psychiatric disorders. Carpenter syndrome, known for over a century now, is a genetic disorder linked to mutations in () gene and associated with intellectual disabilities among other symptoms. is also associated with psychiatric disorders. Despite the high genetic conservation and clinical relevance, the functions of remain largely uncharacterized. Patients with intellectual disabilities and psychiatric diseases often have an underlying defect in synaptic structure and function. This work defines the role of the fly homolog of human , , in glutamatergic synapse growth, organization, and function and provide insights into potential functions of in human central synapses and synaptic mechanisms that may underlie psychiatric disorders and intellectual disabilities seen in Carpenter syndrome.
Topics: Acrocephalosyndactylia; Animals; Drosophila; Drosophila Proteins; EGF Family of Proteins; Female; Humans; Intellectual Disability; Male; Membrane Proteins; Mutation; Receptors, Cell Surface; Synapses
PubMed: 35944997
DOI: 10.1523/JNEUROSCI.0442-22.2022 -
Genes Jun 2022Craniosynostosis are a heterogeneous group of genetic conditions characterized by the premature fusion of the skull bones. The most common forms of craniosynostosis are...
Craniosynostosis are a heterogeneous group of genetic conditions characterized by the premature fusion of the skull bones. The most common forms of craniosynostosis are Crouzon, Apert and Pfeiffer syndromes. They differ from each other in various additional clinical manifestations, e.g., syndactyly is typical of Apert and rare in Pfeiffer syndrome. Their inheritance is autosomal dominant with incomplete penetrance and one of the main genes responsible for these syndromes is FGFR2, mapped on chromosome 10, encoding fibroblast growth factor receptor 2. We report an FGFR2 gene variant in a mother and daughter who present with different clinical features of Crouzon syndrome. The daughter is more severely affected than her mother, as also verified by a careful study of the face and oral cavity. The c.1032G>A transition in exon 8, already reported as a synonymous p.Ala344 = variant in Crouzon patients, also activates a new donor splice site leading to the loss of 51 nucleotides and the in-frame removal of 17 amino acids. We observed lower FGFR2 transcriptional and translational levels in the daughter compared to the mother and healthy controls. A preliminary functional assay and a molecular modeling added further details to explain the discordant phenotype of the two patients.
Topics: Acrocephalosyndactylia; Craniosynostoses; Female; Humans; Mothers; Phenotype; Receptor, Fibroblast Growth Factor, Type 2
PubMed: 35885943
DOI: 10.3390/genes13071161 -
Circulation. Arrhythmia and... Aug 2020Long QT syndrome has been associated with sudden cardiac death likely caused by early afterdepolarizations (EADs) and polymorphic ventricular tachycardias (PVTs)....
BACKGROUND
Long QT syndrome has been associated with sudden cardiac death likely caused by early afterdepolarizations (EADs) and polymorphic ventricular tachycardias (PVTs). Suppressing the late sodium current (I) may counterbalance the reduced repolarization reserve in long QT syndrome and prevent EADs and PVTs.
METHODS
We tested the effects of the selective I blocker GS967 on PVT induction in a transgenic rabbit model of long QT syndrome type 2 using intact heart optical mapping, cellular electrophysiology and confocal Ca imaging, and computer modeling.
RESULTS
GS967 reduced ventricular fibrillation induction under a rapid pacing protocol (n=7/14 hearts in control versus 1/14 hearts at 100 nmol/L) without altering action potential duration or restitution and dispersion. GS967 suppressed PVT incidences by reducing Ca-mediated EADs and focal activity during isoproterenol perfusion (at 30 nmol/L, n=7/12 and 100 nmol/L n=8/12 hearts without EADs and PVTs). Confocal Ca imaging of long QT syndrome type 2 myocytes revealed that GS967 shortened Ca transient duration via accelerating Na/Ca exchanger (I)-mediated Ca efflux from cytosol, thereby reducing EADs. Computer modeling revealed that I potentiates EADs in the long QT syndrome type 2 setting through (1) providing additional depolarizing currents during action potential plateau phase, (2) increasing intracellular Na (Na) that decreases the depolarizing I thereby suppressing the action potential plateau and delaying the activation of slowly activating delayed rectifier K channels (I), suggesting important roles of I in regulating Na.
CONCLUSIONS
Selective I blockade by GS967 prevents EADs and abolishes PVT in long QT syndrome type 2 rabbits by counterbalancing the reduced repolarization reserve and normalizing Na. Graphic Abstract: A graphic abstract is available for this article.
Topics: Action Potentials; Animals; Animals, Genetically Modified; Anti-Arrhythmia Agents; Calcium Signaling; Computer Simulation; Delayed Rectifier Potassium Channels; Disease Models, Animal; Female; Heart Rate; Long QT Syndrome; Male; Models, Cardiovascular; Myocytes, Cardiac; Pyridines; Rabbits; Sodium Channel Blockers; Sodium Channels; Sodium-Calcium Exchanger; Tachycardia, Ventricular; Time Factors; Triazoles; Ventricular Fibrillation
PubMed: 32628505
DOI: 10.1161/CIRCEP.118.006875 -
Indian Journal of Dermatology,... 2010
Topics: Acrocephalosyndactylia; Female; Humans; Infant; Isotretinoin; Male; Young Adult
PubMed: 21079334
DOI: 10.4103/0378-6323.72479 -
Plastic and Reconstructive Surgery Jun 2009Saethre-Chotzen syndrome is a syndromic craniosynostosis defined by a genetic mutation affecting the TWIST1 gene on chromosome 7p21. It is typically associated with... (Review)
Review
BACKGROUND
Saethre-Chotzen syndrome is a syndromic craniosynostosis defined by a genetic mutation affecting the TWIST1 gene on chromosome 7p21. It is typically associated with unicoronal or bicoronal synostosis, eyelid ptosis, dysmorphic external ears, and other variable facial and limb abnormalities. Surgical management of the craniosynostosis addresses the calvarial deformity and may relieve or reduce the risk of intracranial hypertension. The aim of this study was to assess surgical intervention, with particular consideration of the reoperation rate for intracranial hypertension, in Saethre-Chotzen syndrome patients.
METHODS
A retrospective case note analysis was performed on all patients with a confirmed TWIST1 gene abnormality who attended the Oxford Craniofacial Unit over a 15-year period. Each patient's mutation and clinical features were recorded. Surgical intervention and sequelae were examined in greater detail.
RESULTS
Thirty-four patients with genetically confirmed Saethre-Chotzen syndrome were identified. All had craniosynostosis (bicoronal, 76 percent; unicoronal, 18 percent; bicoronal and sagittal, 6 percent), and the majority had eyelid ptosis, low frontal hairline, and external ear anomalies. Thirty-one patients had received surgical intervention. Nine of 26 patients (35 percent) with at least 12 months of follow-up after primary intervention and eight of 19 patients (42 percent) with at least 5 years of follow-up developed intracranial hypertension necessitating secondary calvarial surgery.
CONCLUSIONS
Despite standard surgical intervention, patients with Saethre-Chotzen syndrome have a high rate (35 to 42 percent) of recurrent intracranial hypertension necessitating further surgical expansion. All patients with either bicoronal synostosis or unicoronal synostosis with syndromic features should be screened for TWIST1 mutations, as this confers a greater risk than nonsyndromic synostosis of the same sutures. Regular follow-up throughout the childhood years is essential.
Topics: Acrocephalosyndactylia; Child, Preschool; Craniosynostoses; Female; Gene Deletion; Humans; Infant; Intracranial Hypertension; Male; Nuclear Proteins; Point Mutation; Recurrence; Reoperation; Retrospective Studies; Twist-Related Protein 1
PubMed: 19483581
DOI: 10.1097/PRS.0b013e3181a3f391 -
American Journal of Ophthalmology Case... Jul 2016We report here a newborn male infant with striking features consistent with severe Pfeiffer syndrome type II, including cloverleaf skull deformity with pansynostosis,...
PURPOSE
We report here a newborn male infant with striking features consistent with severe Pfeiffer syndrome type II, including cloverleaf skull deformity with pansynostosis, extreme proptosis, upper extremity contractures, broad big toes and thumbs with varus deviation and genetic mutation in the FGFR2 gene. The authors review the ophthalmic complications in Pfeiffer syndrome and discuss the unique surgical strategies used for obtaining adequate corneal coverage in these unique patients.
OBSERVATIONS
Ophthalmic considerations in Type 2 Pfeiffer Syndrome include vision loss secondary to increased intracranial pressure, and extreme proptosis as a result of orbitostenosis and midfacial retrusion. Our patient has undergone multiple ophthalmic/oculoplastic, neurosurgical, and midfacial surgeries as a result of corneal deterioration due to extreme exorbitism.
CONCLUSIONS AND IMPORTANCE
It is important for ophthalmologists to be aware of the ophthalmic complications associated with patients with craniosynostosis syndromes. Our case identifies the importance of close communication between ophthalmology and plastic reconstructive surgery to help formulate the most successful plan in treating corneal decompensation and proptosis in Pfeiffer Syndrome patients.
PubMed: 29503887
DOI: 10.1016/j.ajoc.2016.04.001 -
Journal of Medical Genetics Aug 1976A 5-year-old boy and his father with Pfeiffer syndrome are described. They had acrocephaly, hypertelorism, antimongoloid slant of the palpebral fissures, protrusion of...
A 5-year-old boy and his father with Pfeiffer syndrome are described. They had acrocephaly, hypertelorism, antimongoloid slant of the palpebral fissures, protrusion of the eyes, large and broad nose, small mandible, irregularly placed teeth, additional upper canine, high-arched palate, partial syndactyly of fingers and toes, brachydactyly of toes, valgus deformity of hypertrophied triangular great toes, broad phalanges of the great toes and broad first metatarsals, accessory epiphyses lateral to the interphalangeal joint of the great toes, and normal intelligence. To our knowledge, this is the first family in which the syndrome is almost totally confined to the head and feet--it spares the upper limbs except for partial skin syndactyly between the fingers--and the third family showing inheritance through three successive generations suggesting an autosomal dominant mode of inheritance. The published papers are reviewed and the clinical and x-ray signs are tabulated.
Topics: Acrocephalosyndactylia; Adult; Child, Preschool; Foot; Humans; Male; Pedigree; Radiography; Skull
PubMed: 957376
DOI: 10.1136/jmg.13.4.277 -
Developmental Dynamics : An Official... Oct 2022Major cell-to-cell signaling pathways, such as the fibroblast growth factors and their four receptors (FGF/FGFR), are conserved across a variety of animal forms....
BACKGROUND
Major cell-to-cell signaling pathways, such as the fibroblast growth factors and their four receptors (FGF/FGFR), are conserved across a variety of animal forms. FGF/FGFRs are necessary to produce several "vertebrate-specific" structures, including the vertebrate head. Here, we examine the effects of the FGFR2 S252W mutation associated with Apert syndrome on patterns of cranial integration. Our data comprise micro-computed tomography images of newborn mouse skulls, bred to express the Fgfr2 S252W mutation exclusively in either neural crest or mesoderm-derived tissues, and mice that express the Fgfr2 S252W mutation ubiquitously.
RESULTS
Procrustes-based methods and partial least squares analysis were used to analyze craniofacial integration patterns. We found that deviations in the direction and degree of integrated shape change across the mouse models used in our study were potentially driven by the modular variation generated by differing expression of the Fgfr2 mutation in cranial tissues.
CONCLUSIONS
Our overall results demonstrate that covariation patterns can be biased by the spatial distribution and magnitude of variation produced by underlying developmental-genetic mechanisms that often impact the phenotype in disproportionate ways.
Topics: Acrocephalosyndactylia; Animals; Disease Models, Animal; Fibroblast Growth Factors; Mice; Mutation; Receptor, Fibroblast Growth Factor, Type 2; Skull; X-Ray Microtomography
PubMed: 35582939
DOI: 10.1002/dvdy.498 -
Genetics in Medicine : Official Journal... Feb 2019Among children with FGFR2-associated Pfeiffer syndrome, those with the W290C pathogenic variant (PV) are reported to have the worst clinical outcomes. Mortality is high,...
A genotype-specific surgical approach for patients with Pfeiffer syndrome due to W290C pathogenic variant in FGFR2 is associated with improved developmental outcomes and reduced mortality.
PURPOSE
Among children with FGFR2-associated Pfeiffer syndrome, those with the W290C pathogenic variant (PV) are reported to have the worst clinical outcomes. Mortality is high, and severe neurocognitive impairment has been reported in all surviving patients. However, it is unclear whether these poor outcomes are an unavoidable consequence of the PV itself, or could be improved with a genotype-specific treatment approach. The purpose of this report is to describe the more intensive surgical approach used for each of the three patients with W290C PV in FGFR2 at our center, all of whom survived and have normal neurocognitive functioning.
METHODS
Retrospective chart review.
RESULTS
In contrast to other patients with Pfeiffer syndrome at our center, all three patients who were subsequently found to have a W290C PV required a similar and more aggressive approach based on early cephalocranial disproportion. In contrast to previously reported W290C cases, each of our three patients survived and demonstrate normal neurocognitive functioning.
CONCLUSION
While previously reported outcomes in W290C-associated Pfeiffer syndrome have been extremely poor, we present three patients who underwent an intensive surgical approach and have normal development. This suggests that a personalized and aggressive surgical approach for children with W290C PV may dramatically improve clinical outcome.
Topics: Acrocephalosyndactylia; Child; Child, Preschool; Cohort Studies; Female; Genotype; Humans; Infant; Infant, Newborn; Mutation; Receptor, Fibroblast Growth Factor, Type 2; Retrospective Studies; Surgical Procedures, Operative; Treatment Outcome
PubMed: 29915381
DOI: 10.1038/s41436-018-0073-x -
Journal of AAPOS : the Official... Feb 2024To better characterize the correlation of bony orbital dysmorphology with strabismus in craniosynostosis.
PURPOSE
To better characterize the correlation of bony orbital dysmorphology with strabismus in craniosynostosis.
METHODS
The medical records of patients with craniosynostosis with and without strabismus seen at Rady Children's Hospital (San Diego, CA) from March 2020 to January 2022 were reviewed retrospectively in this masked, case-control study. Computed tomography scans of the orbits were analyzed to obtain dimensions of the orbital entrance and orbital cone. Primary outcome was correlation of strabismus with orbital measurements.
RESULTS
A total of 30 orbits from 15 patients with strabismus and 15 controls were included. Craniofacial disorders included in the study were nonsyndromic craniosynostosis (63%), Crouzon syndrome (13%), Apert syndrome (13%), and Pfeiffer syndrome (10%). Orbital index (height:width ratio) (P = 0.01) and medial orbital wall angle (P = 0.04) were found to differ significantly between the strabismus and control groups.
CONCLUSIONS
In our small cohort, bony orbital dimensions, including the ratio of orbital height to width and bowing of the medial orbital wall, were associated with strabismus in craniosynostosis.
Topics: Child; Humans; Case-Control Studies; Retrospective Studies; Craniosynostoses; Acrocephalosyndactylia; Strabismus; Orbit
PubMed: 38219920
DOI: 10.1016/j.jaapos.2023.10.006