Role of primary cilia and Hedgehog signaling in craniofacial features of Ellis–van Creveld syndrome

Thomas, Davis C.; Moorthy, Janani Dakshina; Prabhakar, Vaishnavi; Ajayakumar, Ahana; Pitchumani, Priyanka Kodaganallur

doi:10.1002/ajmg.c.31969

Cited by 5 publications

(6 citation statements)

References 80 publications

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“…In addition, mutations in the WDR35 gene have been associated to clinical features similar to these two syndromes [ 8 , 15 , 19 ]. The EVC / EVC2 genes encode transmembrane proteins that are located in the basal zone of the primary cilium and that play an important role in the activation and function of the Hedgehog pathway [ 20 , 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of Compound Heterozygous EVC2 Gene Variants in Two Mexican Families with Ellis–van Creveld Syndrome

Negrete-Torres

Chima-Galán

Sierra-López

et al. 2023

Genes

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Background: Ellis–van Creveld syndrome (EvCS) is an autosomal recessive ciliopathy with a disproportionate short stature, polydactyly, dystrophic nails, oral defects, and cardiac anomalies. It is caused by pathogenic variants in the EVC or EVC2 genes. To obtain further insight into the genetics of EvCS, we identified the genetic defect for the EVC2 gene in two Mexican patients. Methods: Two Mexican families were enrolled in this study. Exome sequencing was applied in the probands to screen potential genetic variant(s), and then Sanger sequencing was used to identify the variant in the parents. Finally, a prediction of the three-dimensional structure of the mutant proteins was made. Results: One patient has a compound heterozygous EVC2 mutation: a novel heterozygous variant c.519_519 + 1delinsT inherited from her mother, and a heterozygous variant c.2161delC (p.L721fs) inherited from her father. The second patient has a previously reported compound heterozygous EVC2 mutation: nonsense mutation c.645G > A (p.W215*) in exon 5 inherited from her mother, and c.273dup (p.K92fs) in exon 2 inherited from her father. In both cases, the diagnostic was Ellis–van Creveld syndrome. Three-dimensional modeling of the EVC2 protein showed that truncated proteins are produced in both patients due to the generation of premature stop codons. Conclusion: The identified novel heterozygous EVC2 variants, c.2161delC and c.519_519 + 1delinsT, were responsible for the Ellis–van Creveld syndrome in one of the Mexican patients. In the second Mexican patient, we identified a compound heterozygous variant, c.645G > A and c.273dup, responsible for EvCS. The findings in this study extend the EVC2 mutation spectrum and may provide new insights into the EVC2 causation and diagnosis with implications for genetic counseling and clinical management.

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Section: Introductionmentioning

confidence: 99%

Identification of Compound Heterozygous EVC2 Gene Variants in Two Mexican Families with Ellis–van Creveld Syndrome

Negrete-Torres

Chima-Galán

Sierra-López

et al. 2023

Genes

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“…The core of functional chest pain's largest network contains three proteins involved in the hedgehog signaling pathway: evc ciliary complex subunit 2 (EVC2), evc ciliary complex subunit 1 (EVC), and GLI family zinc finger 2 (GLI2) 69 , suggesting a novel role of hedgehog signaling in potentiating functional chest pain in enteric neurons (Figure 5A). These nodes, in addition to serine/threonine kinase 32B (STK32B) and MSX homeobox 1 (MSX1), are associated with developmental defects, including Ellisvan Creveld syndrome 70,71 , where short stature and heart malformations are a common disease manifestation and a patient's cause of death is often due to heart failure 72 .…”

Section: Network Analysis Reveals Dgbi Relevant Molecular Pathwaysmentioning

confidence: 99%

Combined GWAS and single cell transcriptomics uncover the underlying genes and cell types in disorders of gut-brain interaction

Majd

Richter

Samuel

et al. 2023

Preprint

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Disorders of gut-brain interaction (DGBIs), formerly known as functional gastrointestinal disorders, are extremely common and historically difficult to manage. This is largely because their cellular and molecular mechanisms have remained poorly understood and understudied. One approach to unravel the molecular underpinnings of complex disorders such as DGBIs is performing genome wide association studies (GWASs). However, due to the heterogenous and non-specific nature of GI symptoms, it has been difficult to accurately classify cases and controls. Thus, to perform reliable studies, we need to access large patient populations which has been difficult to date. Here, we leveraged the UK Biobank (UKBB) database, containing genetic and medical record data of over half a million individuals, to perform GWAS for five DGBI categories: functional chest pain, functional diarrhea, functional dyspepsia, functional dysphagia, and functional fecal incontinence. By applying strict inclusion and exclusion criteria, we resolved patient populations and identified genes significantly associated with each condition. Leveraging multiple human single-cell RNA-sequencing datasets, we found that the disease associated genes were highly expressed in enteric neurons, which innervate and control GI functions. Further expression and association testing-based analyses revealed specific enteric neuron subtypes consistently linked with each DGBI. Furthermore, protein-protein interaction analysis of each of the disease associated genes revealed protein networks specific to each DGBI, including hedgehog signaling for functional chest pain and neuronal function and neurotransmission for functional diarrhea and functional dyspepsia. Finally, through retrospective medical record analysis we found that drugs that inhibit these networks are associated with an increased disease risk, including serine/threonine kinase 32B drugs for functional chest pain, solute carrier organic anion transporter family member 4C1, mitogen-activated protein kinase 6, and dual serine/threonine and tyrosine protein kinase drugs for functional dyspepsia, and serotonin transporter drugs for functional diarrhea. This study presents a robust strategy for uncovering the tissues, cell types, and genes involved in DGBIs, presenting novel predictions of the mechanisms underlying these historically intractable and poorly understood diseases.

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“…The Hedgehog signalling pathway is deemed pivotal in intraflagellar transport (IFT) that occurs inside primary cilia. Sonic hedgehog (SHH) and primary cilia are known to function in the development of tooth germ (Thomas et al, 2022). Therefore, SHH and cilia proteins can take part in the signalling process and tooth formation.…”

Section: Sonic Hedgehog Pathwaymentioning

confidence: 99%

“…The oral phenotype includes abnormalities in tooth number, structure, morphology, and eruption pattern. And the absence of the first and second molars is most common (Thomas et al, 2022). Another disease with a milder phenotype caused by mutations in EVC or EVC2 is Weyers acrofacial dysostosis or Curry Hall syndrome.…”

Section: Gene Mutations In Crucial Pathways Cause Syndromic Tooth Age...mentioning

confidence: 99%

“…The oral phenotype includes abnormalities in tooth number, structure, morphology, and eruption pattern. And the absence of the first and second molars is most common(Thomas et al, 2022). Another disease with a milder phenotype caused byF I G U R E 2 (a-c) Phenotype of one of our patients with EDA mutation: sparse hair and eyebrows, dry skin with wrinkles and crusta, prominent lips, and oligodontia (only two teeth in the dentition): frontal view (a), dentition (b), panoramic photograph (c); (d-f) phenotype of one of our patients with IP: skin lesions and oligodontia: typical hyperpigmented patterns on the leg (d), dentition with previous restoration (e), panoramic photograph (f); (g-i) phenotype of one of our patients with TP63 mutation: the absence of one central digit of the hand and oligodontia: Split hand (g), dentition (h), and panoramic photograph (i).…”

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confidence: 99%

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Gene mutations and chromosomal abnormalities in syndromes with tooth agenesis

Lan

Dai

et al. 2022

Oral Diseases

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This study aims to review the pathogenic mechanisms and clinical manifestations in syndromes with tooth agenesis (TA). Online Mendelian Inheritance in Man and PubMed databases were searched for a comprehensive review. Previous publications reported complicated aetiologies of syndromic TA. Gene mutations in conserved signalling pathways (WNT, EDA, SHH, FGF, and TGF‐β/BMP) and crucial molecules (PAX9, PIXT2, IRF6, the p53 family, and subunits of RNA polymerase III) are the main causes of syndromic TA. In the process of odontogenesis, antagonistic or synergistic interactions are demonstrated in patients and murine models. Mutations in some genes (WNT10A, WNT10B, AXIN2, ANTXR1, MSX1, EDA, EDAR, and EDARADD) can result in both syndromic and isolated TA. In addition, chromosomal anomalies are also responsible for syndromic TA (Down syndrome, Wolf‐Hirschhorn syndrome, Williams syndrome, and Pierre Robin sequence). The causes and manifestations of syndromic TA are highly complex, and this constitutes a clinical challenge. Mutations in signalling pathways and crucial molecules as well as chromosomal anomalies are responsible for syndromic TA. And there are overlaps between the causative genes of syndromic and isolated TA.

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Role of primary cilia and Hedgehog signaling in craniofacial features of Ellis–van Creveld syndrome

Cited by 5 publications

References 80 publications

Identification of Compound Heterozygous EVC2 Gene Variants in Two Mexican Families with Ellis–van Creveld Syndrome

Identification of Compound Heterozygous EVC2 Gene Variants in Two Mexican Families with Ellis–van Creveld Syndrome

Combined GWAS and single cell transcriptomics uncover the underlying genes and cell types in disorders of gut-brain interaction

Gene mutations and chromosomal abnormalities in syndromes with tooth agenesis

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