Expansion of the spectrum of ITGB6-related disorders to adolescent alopecia, dentogingival abnormalities and intellectual disability

Ansar, Muhammad; Jan, Abid; Santos‐Cortez, Regie Lyn P.; Wang, Xin; Suliman, Muhammad; Acharya, Anushree; Habib, Rabia; Abbe, Izoduwa; Ali, Ghazanfar; Lee, Kwanghyuk; Smith, Joshua D.; Nickerson, Deborah A.; Shendure, Jay; Bamshad, Michael J.; Ahmad, Wasim; Leal, Suzanne M.

doi:10.1038/ejhg.2015.260

Cited by 19 publications

(9 citation statements)

References 20 publications

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“…Patients with mutations in ITGB6 have since been reported (MIM #616221) with either hypomineralized pitted enamel, similar to that reported in the Itgb6 null mouse (Poulter et al, 2014a ), or hypoplastic enamel with a rough surface (Wang et al, 2014b ), both recessively inherited. More recently, Ansar et al ( 2015 ) reported a consanguineous family with a homozygous ITGB6 mutation with adolescent alopecia, intellectual disability and dentogingival abnormalities with rough, discolored enamel. However, it is unclear if these additional phenotypes result from the ITGB6 variant or are co-segregating, for example, due to an undetected copy number variant.…”

Section: The Genetics Of Amelogenesis Imperfectamentioning

confidence: 99%

Amelogenesis Imperfecta; Genes, Proteins, and Pathways

et al. 2017

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Amelogenesis imperfecta (AI) is the name given to a heterogeneous group of conditions characterized by inherited developmental enamel defects. AI enamel is abnormally thin, soft, fragile, pitted and/or badly discolored, with poor function and aesthetics, causing patients problems such as early tooth loss, severe embarrassment, eating difficulties, and pain. It was first described separately from diseases of dentine nearly 80 years ago, but the underlying genetic and mechanistic basis of the condition is only now coming to light. Mutations in the gene AMELX, encoding an extracellular matrix protein secreted by ameloblasts during enamel formation, were first identified as a cause of AI in 1991. Since then, mutations in at least eighteen genes have been shown to cause AI presenting in isolation of other health problems, with many more implicated in syndromic AI. Some of the encoded proteins have well documented roles in amelogenesis, acting as enamel matrix proteins or the proteases that degrade them, cell adhesion molecules or regulators of calcium homeostasis. However, for others, function is less clear and further research is needed to understand the pathways and processes essential for the development of healthy enamel. Here, we review the genes and mutations underlying AI presenting in isolation of other health problems, the proteins they encode and knowledge of their roles in amelogenesis, combining evidence from human phenotypes, inheritance patterns, mouse models, and in vitro studies. An LOVD resource (http://dna2.leeds.ac.uk/LOVD/) containing all published gene mutations for AI presenting in isolation of other health problems is described. We use this resource to identify trends in the genes and mutations reported to cause AI in the 270 families for which molecular diagnoses have been reported by 23rd May 2017. Finally we discuss the potential value of the translation of AI genetics to clinical care with improved patient pathways and speculate on the possibility of novel treatments and prevention strategies for AI.

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Section: The Genetics Of Amelogenesis Imperfectamentioning

confidence: 99%

Amelogenesis Imperfecta; Genes, Proteins, and Pathways

et al. 2017

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“…In healthy periodontal tissues, both αvβ6 integrin and TGF-β1 are constitutively expressed in the JE 25 , and it is likely that αvβ6 integrin-mediated activation of TGF-β1 is involved in the regulation of the anti-inflammatory response in these tissues. In periodontal disease, the expression of αvβ6 integrin becomes strongly downregulated in the PE, and patients with mutations in the β6 integrin gene can develop severe periodontal disease 25 , 27 . In addition, mice deficient in β6 integrin spontaneously develop periodontal disease that involves PE formation, inflammation and bone loss 25 .…”

Section: Introductionmentioning

confidence: 99%

Suppression of αvβ6 Integrin Expression by Polymicrobial Oral Biofilms in Gingival Epithelial Cells

Koivisto

Pang

et al. 2017

Sci Rep

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Periodontal diseases manifest by the formation of deep pockets between the gingiva and teeth where multispecies bacterial biofilms flourish, causing inflammation and bone loss. Epithelial cell receptor αvβ6 integrin that regulates inflammation by activating the anti-inflammatory cytokine transforming growth factor-β1, is highly expressed in healthy junctional epithelium that connects the gingiva to the tooth enamel. However, its expression is attenuated in human periodontal disease. Moreover, Itgb6 −/− mice display increased periodontal inflammation compared to wild-type mice. We hypothesized that bacterial biofilms present in the periodontal pockets suppress αvβ6 integrin levels in periodontal disease and that this change aggravates inflammation. To this end, we generated three-week-old multi-species oral biofilms in vitro and treated cultured gingival epithelial cells (GECs) with their extracts. The biofilm extracts caused suppression of β6 integrin expression and upregulation of pro-inflammatory cytokines, including interleukin-1β and -6. Furthermore, GECs with β6 integrin siRNA knockdown showed increased interleukin-1β expression, indicating that αvβ6 integrin-deficiency is associated with pro-inflammatory cytokine responsiveness. FSL-1, a synthetic bacterial lipopeptide, also suppressed β6 integrin expression in GECs. Therefore, biofilm components, including lipopeptides, may downregulate αvβ6 integrin expression in the pocket epithelium and thus promote epithelial cell-driven pro-inflammatory response in periodontal disease.

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“…Two cases are illustrative of common themes in medical genomics (Prada et al, 2014;Ansar, 2015;Taylan et al 2016). A non-sense mutation in GRIK2 caused a more complex phenotype than it was previously recognized for this gene.…”

Section: Discussionmentioning

confidence: 99%

Whole Exome Sequencing in Neurogenetic Diagnostic Odysseys: An Argentinian Experience

Córdoba

Rodríguez-Quiroga

Vega

et al. 2016

Preprint

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Clinical variability is a hallmark of neurogenetic disorders. They involve widespread neurological entities such as neuropathies, ataxias, myopathies, mitochondrial encephalopathies, leukodystrophies, epilepsy and intellectual disabilities. Despite the use of considerable time and resources, the diagnostic yield in this field has been disappointingly low. This etiologic search has been called a "diagnostic odyssey" for many families. Whole exome sequencing (WES) has proved to be useful across a variety of genetic disorders, simplifying the odyssey of many patients and their families and leading to subsequent changes in clinical management in a proportion of them. Although a diagnostic yield of about 30% in neurogenetic disorders can be extrapolated from the results of large series that have included other medical conditions as well, there are not specific reports assessing its utility in a setting such as ours: a neurogeneticist led academic group serving in a low-income country.Herein, we report on a series of our first 40 consecutive cases that were selected for WES in a research-based neurogenetics laboratory. We demonstrated the clinical utility of WES in our patient cohort, obtaining a diagnostic yield of 40% (95% CI, 24.8%-55.2%), describing cases in which clinical management was altered, and suggesting the potential cost-effectiveness of WES as a single test by examining the number and types of tests that were performed prior to

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Expansion of the spectrum of ITGB6-related disorders to adolescent alopecia, dentogingival abnormalities and intellectual disability

Cited by 19 publications

References 20 publications

Amelogenesis Imperfecta; Genes, Proteins, and Pathways

Amelogenesis Imperfecta; Genes, Proteins, and Pathways

Suppression of αvβ6 Integrin Expression by Polymicrobial Oral Biofilms in Gingival Epithelial Cells

Whole Exome Sequencing in Neurogenetic Diagnostic Odysseys: An Argentinian Experience

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