scholarly journals Ciliary Signalling and Mechanotransduction in the Pathophysiology of Craniosynostosis

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1073
Author(s):  
Federica Tiberio ◽  
Ornella Parolini ◽  
Wanda Lattanzi
Keyword(s):  
Primary Cilium ◽  
Genetic Basis ◽  
Mendelian Inheritance ◽  
Craniofacial Development ◽  
Cranial Sutures ◽  
Craniofacial Malformation ◽  
Computational Annotation ◽  
Neural Crest Origin ◽  
Disease Associated Genes ◽  
Molecular Signals

Craniosynostosis (CS) is the second most prevalent inborn craniofacial malformation; it results from the premature fusion of cranial sutures and leads to dimorphisms of variable severity. CS is clinically heterogeneous, as it can be either a sporadic isolated defect, more frequently, or part of a syndromic phenotype with mendelian inheritance. The genetic basis of CS is also extremely heterogeneous, with nearly a hundred genes associated so far, mostly mutated in syndromic forms. Several genes can be categorised within partially overlapping pathways, including those causing defects of the primary cilium. The primary cilium is a cellular antenna serving as a signalling hub implicated in mechanotransduction, housing key molecular signals expressed on the ciliary membrane and in the cilioplasm. This mechanical property mediated by the primary cilium may also represent a cue to understand the pathophysiology of non-syndromic CS. In this review, we aimed to highlight the implication of the primary cilium components and active signalling in CS pathophysiology, dissecting their biological functions in craniofacial development and in suture biomechanics. Through an in-depth revision of the literature and computational annotation of disease-associated genes we categorised 18 ciliary genes involved in CS aetiology. Interestingly, a prevalent implication of midline sutures is observed in CS ciliopathies, possibly explained by the specific neural crest origin of the frontal bone.

scholarly journals Molecular Analysis of Gli3, Ihh, Rab23, and Jag1 in a Rabbit Model of Craniosynostosis

2017 ◽  
Vol 55 (3) ◽  
pp. 375-382 ◽  
Author(s):  
James R. Gilbert ◽  
Gwen M. Taylor ◽  
Joseph E. Losee ◽  
Mark P. Mooney ◽  
Gregory M. Cooper
Keyword(s):  
Family Member ◽  
Genetic Basis ◽  
Rabbit Model ◽  
Craniofacial Development ◽  
Cranial Sutures ◽  
Nucleotide Polymorphisms ◽  
Ras Oncogene ◽  
Wild Type ◽  
Protein Coding ◽  
Coding Regions

Objective: Craniosynostosis (CS) involves the premature fusion of one or more cranial sutures. The etiology of CS is complex and mutations in more than 50 distinct genes have been causally linked to the disorder. Many of the genes that have been associated with CS in humans play an essential role in tissue patterning and early craniofacial development. Among these genes are members of the Hedgehog (HH) and Notch signal transduction pathways, including the GLI family member Gli3, Indian Hedgehog ( Ihh), the RAS oncogene family member Rab23, and the Notch ligand JAGGED1 ( Jag1). We have previously described a colony of rabbits with a heritable pattern of coronal suture synostosis, although the genetic basis for synostosis within this model remains unknown. The present study was performed to determine if coding errors in Gli3, Ihh, Rab23, or Jag1 could be causally linked to craniosynostosis in this unique animal model. Design: Sequencing of cDNA templates was performed using samples obtained from wild-type and craniosynostotic rabbits. Results: Several nucleotide polymorphisms were identified in Gli3, Ihh, and Rab23, although these variants failed to segregate by phenotype. No nucleotide polymorphisms were identified in Jag1. Conclusions: These data indicate that the causal locus for heritable craniosynostosis in this rabbit model is not located within the protein coding regions of Gli3, Ihh, Rab23, or Jag1.

Genetics in Ophthalmology

2020 ◽  
pp. 44-45
Author(s):  
А.Ю. Рудник ◽  
М.А. Федяков ◽  
О.С. Глотов
Keyword(s):  
Genetic Basis ◽  
Genetic Diseases ◽  
Mendelian Inheritance ◽  
Diagnostic Screening ◽  
Online Mendelian Inheritance ◽  
Clinical Diagnostic ◽  
Omim Database

На сегодняшний день в базе данных Online Mendelian Inheritance in Man (OMIM) описано более 6613 заболеваний и фенотипов, 4241 имеют доказанную генетическую основу, не менее 45% вкючают офтальмологические проявления. В статье приведен ряд клинический примеров пациентов с офтальмологическими симптомами различных генетических заболеваний (алкаптонурия, болезнь Штаргардта, синдром микроцефалии с или без хориоретинопатии; астроцитарная гамартома) с целью демонстрации эффективного клинико-диагностического скрининга генетической патологии у пациентов. So far, the Online Mendelian Inheritance in Man (OMIM) database describes more than 6613 diseases and phenotypes, 4241 have a proven genetic basis, 45% of which are combined with ophthalmological manifestations. The article provides a number of clinical examples of patients with ophthalmological manifestations of various genetic diseases (alcaptonuria, Stadgart ‘s disease, microcephaly syndrome with or without choriretinopathy; Astrocytic gamartoma) to demonstrate effective clinical-diagnostic screening of genetic pathology in patients.

scholarly journals Epistatic Control of Non-Mendelian Inheritance in Mouse Interspecific Crosses

Genetics ◽  
1996 ◽  
Vol 143 (4) ◽  
pp. 1739-1752 ◽  
Author(s):  
Xavier Montagutelli ◽  
Rowena Turner ◽  
Joseph H Nadeau
Keyword(s):  
X Chromosome ◽  
Genetic Basis ◽  
Mendelian Inheritance ◽  
The Other ◽  
Interspecific Crosses ◽  
Chromosome 2 ◽  
Mus Spretus ◽  
F1 Hybrid ◽  
Strong Deviation ◽  
Marker Loci

Abstract Strong deviation of allele frequencies from Mendelian inheritance favoring Mus spretus-derived alleles has been described previously for X-linked loci in four mouse interspecific crosses. We reanalyzed data for three of these crosses focusing on the location of the gene(s) controlling deviation on the X chromosome and the genetic basis for incomplete deviation. At least two loci control deviation on the X chromosome, one near Xist (the candidate gene controlling X inactivation) and the other more centromerically located. In all three crosses, strong epistasis was found between loci near Xist and marker loci on the central portion of chromosome 2. The mechanism for this deviation from Mendelian expectations is not yet known but it is probably based on lethality of embryos carrying particular combinations of alleles rather than true segregation distortion during oogenesis in F1 hybrid females.

Natural Polymorphisms in a Pair of NSP2 Homoeologs Can Cause Loss of Nodulation in Peanut

2020 ◽  
Author(s):  
Ze Peng ◽  
Huiqiong Chen ◽  
Lubin Tan ◽  
Hongmei Shu ◽  
Rajeev K Varshney ◽  
...  
Keyword(s):  
Genetic Basis ◽  
Molecular Mechanisms ◽  
Root Nodules ◽  
Germplasm Collection ◽  
Mendelian Inheritance ◽  
Legume Crop ◽  
Arachis Hypogaea L ◽  
Transcription Factor Genes ◽  
Cultivated Peanut ◽  
Microbial Symbiosis

Abstract Microbial symbiosis in legumes is achieved through nitrogen-fixing root nodules, which is important for sustainable agriculture. The molecular mechanisms underlying development of root nodules in polyploid legume crops are largely understudied. Through map-based cloning and QTL-seq approaches, we identified a pair of homoeologous GRAS transcription factor genes, Nodulation Signaling Pathway 2 (AhNSP2-B07 or Nb) and AhNSP2-A08 (Na), controlling nodulation in cultivated peanut (Arachis hypogaea L.), an allotetraploid legume crop, which exhibited non-Mendelian and Mendelian inheritance, respectively. The segregation of nodulation in the progeny of Nananbnb genotypes followed a 3:1 Mendelian ratio, in contrast to the 5:3 ~ 1:1 non-Mendelian ratio for nanaNbnb genotypes. Additionally, a much higher frequency of the nb allele (13%) than the na allele (4%) exists in the peanut germplasm collection, suggesting that Nb is less essential than Na in nodule organogenesis. Our findings provided the genetic basis of naturally occurred non-nodulating peanut plants, which can be potentially used for nitrogen fixation improvement in peanut. Furthermore, the results provided implications and insights into the evolution of homoeologous genes in allopolyploid species.

scholarly journals Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and common BMP2 alleles

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Andrew T Timberlake ◽  
Jungmin Choi ◽  
Samir Zaidi ◽  
Qiongshi Lu ◽  
Carol Nelson-Williams ◽  
...  
Keyword(s):  
Epistatic Interaction ◽  
Osteoblast Differentiation ◽  
Genetic Basis ◽  
De Novo ◽  
Genetic Interaction ◽  
Cranial Sutures ◽  
Incomplete Penetrance ◽  
Common Variants ◽  
Neurologic Outcomes ◽  
Metopic Craniosynostosis

Premature fusion of the cranial sutures (craniosynostosis), affecting 1 in 2000 newborns, is treated surgically in infancy to prevent adverse neurologic outcomes. To identify mutations contributing to common non-syndromic midline (sagittal and metopic) craniosynostosis, we performed exome sequencing of 132 parent-offspring trios and 59 additional probands. Thirteen probands (7%) had damaging de novo or rare transmitted mutations in SMAD6, an inhibitor of BMP – induced osteoblast differentiation (p<10−20). SMAD6 mutations nonetheless showed striking incomplete penetrance (<60%). Genotypes of a common variant near BMP2 that is strongly associated with midline craniosynostosis explained nearly all the phenotypic variation in these kindreds, with highly significant evidence of genetic interaction between these loci via both association and analysis of linkage. This epistatic interaction of rare and common variants defines the most frequent cause of midline craniosynostosis and has implications for the genetic basis of other diseases.

Genetics in Pediatric Dentistry

2019 ◽  
Author(s):  
Rohit Kulshrestha
Keyword(s):  
Genetic Screening ◽  
Genetic Basis ◽  
Pediatric Dentistry ◽  
Craniofacial Development ◽  
Dental Anomalies ◽  
Great Role ◽  
Oral Cancers ◽  
Dental Diseases ◽  
Screening And Diagnosis ◽  
Dental Malocclusion

Genetics plays a very important role in normal craniofacial development, abnormal dental anomalies, and different dental diseases such as dental caries, periodontitis, and dental malocclusion. Even it has a great role in different oral cancers also. Very little importance is given for genetic screening and diagnosis of dental diseases. This article attempts to gather insight about different dental diseases and their genetic basis, the need for genetic screening and testing to avoid future problems.

Genetic epidemiology 1: behavioural genetics

2003 ◽  
pp. 317-334
Author(s):  
Frühling Rijsdijk ◽  
Pak Sham
Keyword(s):  
Population Genetics ◽  
Environmental Factors ◽  
Genetic Basis ◽  
Genetic Factors ◽  
Genetic Mutation ◽  
Mendelian Inheritance ◽  
Behavioural Genetics ◽  
Mendelian Disorders ◽  
Genetics Research ◽  
Genetic And Environmental Factors

Behavioural genetics is the study of the genetic basis of behavioural traits including both psychiatric disorders and ‘normal’ personality dimensions. Behavioural genetics derives its theoretical basis from population genetics. Soon after the laws of Mendelian inheritance were re-discovered in 1900, the implications of these laws on the genetic properties of populations were worked out. Such properties include segregation ratios, genotypic frequencies in random mating populations, the effect of population structure and systems of mating, the impact of selection, the partitioning of genetic variance, and the genetic correlation between relatives. Some appreciation of population genetics is necessary for a deep understanding of behavioural genetics. Because of the complexity of behavioural traits, genetic factors cannot be regarded in isolation, or as static. Instead, it is important to consider: (i) the relative contributions of genetic and environmental factors, (ii) the interplay between genetic and environmental factors, and (iii) the changing role of genetic factors in different stages of development from infancy to old age. The major study designs in behavioural genetics will be discussed in this chapter, namely family studies, twin studies, and adoption studies. Behavioural genetics, augmented by molecular genetics has the potential to identify specific genetic variants which influence behaviour. This will be considered in detail in Chapter 14. Mendelian inheritance Gregor Mendel first demonstrated the genetic basis of biological inheritance by studies of simple all-or-none traits in the garden pea. These traits were particularly revealing because they were completely determined by the genotype at a single chromosomal locus. Diseases caused by genetic mutation at a single locus are commonly called Mendelian or single-gene disorders. A dominant disorder is expressed when an individual has one or two copies of the mutant allele, whereas a recessive disorder is expressed only when both alleles at the locus are the mutant variant. Examples of Mendelian disorders of clinical significance in psychiatry are Huntington's disease and fragile X syndrome. Mendelian disorders tend to be relatively rare because they are usually subjected to severe negative selective pressure, due to their increased mortality. Most common disorders and continuous traits of interest in psychiatry have an aetiology involving multiple genetic and environmental factors. Categorical and dimensional traits Behavioural genetics is rooted in both psychiatry and psychology. Psychiatrists traditionally adopt a medical model where diseases are defined as categorical entities and diagnoses are either present or absent. Psychologists on the other hand prefer quantitative measures of cognitive ability, personality and other traits. The methodology of behavioural genetics research reflects this duality, although there is a trend to integrate the two approaches, especially for traits such as anxiety and depression where both diagnostic criteria and quantitative measures exist.

scholarly journals Cranial sutures work collectively to distribute strain throughout the reptile skull

2013 ◽  
Vol 10 (86) ◽  
pp. 20130442 ◽  
Author(s):  
Neil Curtis ◽  
M. E. H. Jones ◽  
S. E. Evans ◽  
P. O'Higgins ◽  
M. J. Fagan
Keyword(s):  
Growth And Development ◽  
Bone Growth ◽  
Normal Growth ◽  
Craniofacial Development ◽  
Abnormal Development ◽  
Cranial Sutures ◽  
Modelling Techniques ◽  
Suture Fusion ◽  
High Level ◽  
First Time

The skull is composed of many bones that come together at sutures. These sutures are important sites of growth, and as growth ceases some become fused while others remain patent. Their mechanical behaviour and how they interact with changing form and loadings to ensure balanced craniofacial development is still poorly understood. Early suture fusion often leads to disfiguring syndromes, thus is it imperative that we understand the function of sutures more clearly. By applying advanced engineering modelling techniques, we reveal for the first time that patent sutures generate a more widely distributed, high level of strain throughout the reptile skull. Without patent sutures, large regions of the skull are only subjected to infrequent low-level strains that could weaken the bone and result in abnormal development. Sutures are therefore not only sites of bone growth, but could also be essential for the modulation of strains necessary for normal growth and development in reptiles.

scholarly journals Ciliopathy Protein Tmem107 Plays Multiple Roles in Craniofacial Development

2017 ◽  
Vol 97 (1) ◽  
pp. 108-117 ◽  
Author(s):  
P. Cela ◽  
M. Hampl ◽  
N.A. Shylo ◽  
K.J. Christopher ◽  
M. Kavkova ◽  
...  
Keyword(s):  
Primary Cilium ◽  
Broad Spectrum ◽  
Cleft Lip ◽  
Primary Cilia ◽  
Transmembrane Protein ◽  
Joubert Syndrome ◽  
Craniofacial Development ◽  
Special Focus ◽  
Acetylated Tubulin ◽  
Head Development

A broad spectrum of human diseases called ciliopathies is caused by defective primary cilia morphology or signal transduction. The primary cilium is a solitary organelle that responds to mechanical and chemical stimuli from extracellular and intracellular environments. Transmembrane protein 107 (TMEM107) is localized in the primary cilium and is enriched at the transition zone where it acts to regulate protein content of the cilium. Mutations in TMEM107 were previously connected with oral-facial-digital syndrome, Meckel-Gruber syndrome, and Joubert syndrome exhibiting a range of ciliopathic defects. Here, we analyze a role of Tmem107 in craniofacial development with special focus on palate formation, using mouse embryos with a complete knockout of Tmem107. Tmem107–/– mice were affected by a broad spectrum of craniofacial defects, including shorter snout, expansion of the facial midline, cleft lip, extensive exencephaly, and microphthalmia or anophthalmia. External abnormalities were accompanied by defects in skeletal structures, including ossification delay in several membranous bones and enlargement of the nasal septum or defects in vomeronasal cartilage. Alteration in palatal shelves growth resulted in clefting of the secondary palate. Palatal defects were caused by increased mesenchymal proliferation leading to early overgrowth of palatal shelves followed by defects in their horizontalization. Moreover, the expression of epithelial stemness marker SOX2 was altered in the palatal shelves of Tmem107–/– animals, and differences in mesenchymal SOX9 expression demonstrated the enhancement of neural crest migration. Detailed analysis of primary cilia revealed region-specific changes in ciliary morphology accompanied by alteration of acetylated tubulin and IFT88 expression. Moreover, Shh and Gli1 expression was increased in Tmem107–/– animals as shown by in situ hybridization. Thus, TMEM107 is essential for proper head development, and defective TMEM107 function leads to ciliary morphology disruptions in a region-specific manner, which may explain the complex mutant phenotype.

Genomic and plumage variation in Vermivora hybrids

The Auk ◽  
2020 ◽  
Vol 137 (3) ◽  
Author(s):  
Marcella D Baiz ◽  
Gunnar R Kramer ◽  
Henry M Streby ◽  
Scott A Taylor ◽  
Irby J Lovette ◽  
...  
Keyword(s):  
Genetic Basis ◽  
First Generation ◽  
Parental Species ◽  
Face Mask ◽  
Mendelian Inheritance ◽  
Hybrid Index ◽  
Species Identity ◽  
Phenotypic Characters ◽  
Genomic Regions ◽  
Carotenoid Pigmentation

Abstract Hybrids with different combinations of traits can be used to identify genomic regions that underlie phenotypic characters important to species identity and recognition. Here, we explore links between genomic and plumage variation in Blue-winged Warbler x Golden-winged Warbler (Vermivora cyanoptera x V. chrysoptera) hybrids, which have traditionally been categorized into 2 discrete types. “Lawrence’s” hybrids are yellow overall, similar to Blue-winged Warblers, but exhibit the black throat patch and face mask of Golden-winged Warblers. “Brewster’s” hybrids are similar to Golden-winged Warblers, but lack the black throat patch and face mask, and sometimes have yellow on their underparts. Previous studies hypothesized that (1) first generation hybrids are of the Brewster’s type and can be distinguished by the amount of yellow on their underparts, and that (2) the throat patch/mask phenotype is consistent with Mendelian inheritance and controlled by variation in a locus near the Agouti-signaling protein (ASIP) gene. We addressed these hypotheses using whole genome re-sequencing of parental and hybrid individuals. We found that Brewster’s hybrids had genomic hybrid index scores indicating this phenotype can arise by majority ancestry from either parental species, that their plumage varied in levels of carotenoid pigmentation, and individuals captured in multiple years grew consistently less yellow over time. Variation in carotenoid pigmentation showed little relationship with genomic hybrid index score and is thus inconsistent with previous hypotheses that first generation hybrids can be distinguished by the amount of yellow in their plumage. Our results also confirm that variation near ASIP underlies the throat patch phenotype, which we refined to an ~10–15 Kb region upstream of the coding sequence. Overall, our results support the notion that traditional categorization of hybrids as either Lawrence’s or Brewster’s oversimplifies continuous variation in carotenoid pigmentation, and its inferred underlying genetic basis, and is based primarily on one discrete trait, which is the throat patch/mask phenotype.

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