Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this review, we describe the current knowledge and the advances in research on human genes whose defect leads to dental anomalies. Recently, it was demonstrated that a missense mutation of a human homeobox MSX1 gene causes autosomal dominant agenesis of second premolars and third molars. X-linked anhidrotic ectodermal dysplasia (EDA), characterized by abnormal hair, teeth, and sweat glands, was demonstrated to be caused by a mutation in a novel transmembrane protein gene that is expressed in epithelial cells and in other adult and fetal tissues. The autosomal dominant Rieger syndrome (RS) manifests hypodontia, adontia, iridogoniodysgenesis and umbilical anomalies. Recently, a novel homeobox gene, RIEG, of Otx family was cloned as a causal gene of RS. The several mutations have been reported on the genes causing hypophosphatasia, which is characterized by defective mineralization of the skeletal and dental structures. An autosomal dominant dentinogenesis imperfecta (DI) is mostly associated with osteogenesis imperfecta (OI). Most patients with DI have mutations in either the COL1A1 or COL1A2 genes of type I collagen. Amelogenesis imperfecta (AI) is a diverse group of hereditary disorders characterized by a variety of developmental enamel defects including hypoplasia and hypomineralization, some of which have been revealed to be associated with defective amelogenin genes.
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PMID:[Hereditary diseases with tooth anomalies and their causal genes]. 971 Oct 25

TBX22 belongs to the T-box family of transcription factors and was originally found in an in silico approach designed to identify new genes on the human Xq12-q21 region. Mutations in TBX22 have been reported in families with X-linked cleft palate and ankyloglossia (CPX), but the underlying pathogenetic mechanism remained unknown. We have identified mouse Tbx22 and analyzed its expression during embryogenesis by reverse transcriptase-polymerase chain reaction and in situ hybridization. In mouse embryos, it is expressed in distinct areas of the head, namely the mesenchyme of the inferior nasal septum, the posterior palatal shelf before fusion, the attachment of the tongue, and mesenchymal cells surrounding the eye anlage. The localization in the tongue frenulum perfectly correlates with the ankyloglossia phenotype in CPX. Furthermore, we identified positionally conserved binding sites for transcription factors, two of which have been implicated previously in palatogenesis (MSX1, PRX2).
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PMID:Expression of mouse Tbx22 supports its role in palatogenesis and glossogenesis. 1266 95

Tooth agenesis constitutes one of the most common developmental anomalies in man. Oligodontia is defined as congenital absence of six or more teeth. Based on the studies of our team in cooperation with Peking University Center for Human Disease Genomics in the past five years, this article reviews the current research progress in clinical phenotypes and case collection, epidemiological investigation and etiological genetic studies of oligodontia. The symptoms of oligodontia were classified into syndromic and non-syndromic according to the occurrence of tooth agenesis with or without systemic developmental defects. As for the advancement of theories and techniques of molecular genetics, a number of gene mutations have been identified to be the direct etiological factors causing some specified diseases, especially those with developmental defects. Here, this article summarized the outcomes of molecular genetic study of some cases we collected. Of the systemic oligondontia patients, a new four-base-deletion mutation in PITX2 was identified in a large kindred with typical symptoms of Rieger Syndrome; four different gene mutations in ED1 casing X-linked hypohidrotic ectodermal displasia were found in five nucleus families. Compared with the former, non-syndromic oligodontia has more genetic heterogeneity rather than some specific virulence gene. PAX9 and MSX1 are the identified genes associated with family tooth agenesis without systemic syndrome. Also, in our research, three gene mutations in CBFA1 were detected in four cleidocranial dysplasia families, which is a systemic developmental disease including the symptoms of tooth eruption abnormality and accessory teeth.
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PMID:[Research advances in tooth agenesis]. 1730 18

Familial non-syndromic hypodontia shows a wide phenotypic heterogeneity and inherits in an autosomal-dominant, autosomal-recessive or X-linked mode. Mutations in genes PAX9, MSX1 and AXIN2 have been determined to be associated with autosomal-dominant tooth agenesis. Recent studies in two families showed that X-linked non-syndromic hypodontia resulted from EDA mutations. In this study, a novel EDA mutation (Thr338Met) that results in X-linked non-syndromic hypodontia in a Chinese family was identified. The patterns of tooth agenesis in these related subjects with defined EDA mutation were analyzed using comparative statistical analysis of tooth agenesis in EDA, MSX1 and PAX9. Statistically significant differences (p<0.001) were observed at eight positions. The resulting data of congenital absence of maxillary and mandibular central incisors, lateral incisors and canines, with the high possibility of persistence of maxillary and mandibular first permanent molars, appears as a pattern of tooth agenesis, suggesting the presence of an EDA mutation.
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PMID:Novel EDA mutation resulting in X-linked non-syndromic hypodontia and the pattern of EDA-associated isolated tooth agenesis. 1865 36

X-linked mental retardation (XLMR) is a complex human disease that causes intellectual disability. Causal mutations have been found in approximately 90 X-linked genes; however, molecular and biological functions of many of these genetically defined XLMR genes remain unknown. PHF8 (PHD (plant homeo domain) finger protein 8) is a JmjC domain-containing protein and its mutations have been found in patients with XLMR and craniofacial deformities. Here we provide multiple lines of evidence establishing PHF8 as the first mono-methyl histone H4 lysine 20 (H4K20me1) demethylase, with additional activities towards histone H3K9me1 and me2. PHF8 is located around the transcription start sites (TSS) of approximately 7,000 RefSeq genes and in gene bodies and intergenic regions (non-TSS). PHF8 depletion resulted in upregulation of H4K20me1 and H3K9me1 at the TSS and H3K9me2 in the non-TSS sites, respectively, demonstrating differential substrate specificities at different target locations. PHF8 positively regulates gene expression, which is dependent on its H3K4me3-binding PHD and catalytic domains. Importantly, patient mutations significantly compromised PHF8 catalytic function. PHF8 regulates cell survival in the zebrafish brain and jaw development, thus providing a potentially relevant biological context for understanding the clinical symptoms associated with PHF8 patients. Lastly, genetic and molecular evidence supports a model whereby PHF8 regulates zebrafish neuronal cell survival and jaw development in part by directly regulating the expression of the homeodomain transcription factor MSX1/MSXB, which functions downstream of multiple signalling and developmental pathways. Our findings indicate that an imbalance of histone methylation dynamics has a critical role in XLMR.
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PMID:Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish brain and craniofacial development. 2062 53

Mutations in the gene encoding the T-box transcription factor TBX22 cause X-linked cleft palate and ankyloglossia in humans. Here we show that Tbx22 expression during facial and palatal development is regulated by FGF and BMP signaling. Our results demonstrate that FGF8 induces Tbx22 in the early face while BMP4 represses and thus restricts its expression. This regulation is conserved between chicken and mouse, although the Tbx22-expression patterns differ considerably between these two species. We suggest that these species-specific differences may result at least in part from differences in the spatiotemporal patterns of BMP activity, but we exclude a direct repression of Tbx22 by the BMP-inducible transcriptional repressor MSX1. Together these findings help to integrate Tbx22 into the molecular network of factors regulating facial development.
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PMID:Regulation of Tbx22 during facial and palatal development. 2084 26

Oligodontia is the developmental absence of more than 5 permanent teeth except for the third molar. Familial oligodontia can occur as an isolated form or as part of a genetic syndrome. Mutations in the MSX1, PAX9, AXIN2, EDA, and WNT10A genes have been identified in familial non-syndromic oligodontia. Ectodermal dysplasia is a group of syndromes involving abnormalities of the ectodermal structures and is comprised of more than 150 different forms. Mutations in the ectodysplasin-A (EDA) gene have been associated with X-linked hypohidrotic ectodermal dysplasia, and partial disruption of the EDA signaling pathway has been shown to cause an isolated form of oligodontia. We identified 2 X-linked oligodontia families and performed mutational analysis of the EDA gene. The mutational analysis revealed 2 novel EDA mutations: c.866G>T, p.Arg289Leu and c.1135T>G, p.Phe379Val (reference sequence NM_001399.4). These mutations were perfectly segregated with oligodontia and curly hair within each family and were not found in the 150 control X-chromosomes with the same ethnic background and in the exome variant server. This study broadens the mutational spectrum of the EDA gene and the understanding of X-linked oligodontia with curly hair.
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PMID:Oligodontia and curly hair occur with ectodysplasin-a mutations. 2448 76

Congenital tooth agenesis in human is characterized by failure of tooth development during tooth organogenesis. 300 genes in mouse and 30 genes in human so far have been known to regulate tooth development. However, candidature of only 5 genes viz. PAX9, MSX1, AXIN2, WNT10A and EDA have been experimentally established for congenitally missing teeth like hypodontia and oligodontia. In this study an Indian family with multiple congenital tooth agenesis was identified. Pattern of inheritance was apparently autosomal dominant type with a rare possibility to be X-linked. Whole genome sequencing of two affected individuals was carried out which revealed 119 novel non-synonymous single nucleotide variations (SNVs) distributed among 117 genes. Out of these only one variation (c.956G>T) located at exon 9 of X-linked EDA gene was considered as pathogenic and validated among all the affected and unaffected family members and unrelated controls. This variation leads to p.Ser319Ile change in the TNF homology domain of EDA (transcript variant 1) protein. In silico analysis predicts that this Ser319 is well conserved across different vertebrate species and a part of putative receptor binding site. Structure based homology modeling predicts that this amino acid residue along with four other amino acid residues nearby, those when mutated known to cause selective tooth agenesis, form a cluster that may have functional significance. Taken together these results suggest that c.956G>T (p.Ser319Ile) mutation plausibly reduces the receptor binding activity of EDA leading to distinct tooth agenesis in this family.
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PMID:Whole genome sequencing reveals novel non-synonymous mutation in ectodysplasin A (EDA) associated with non-syndromic X-linked dominant congenital tooth agenesis. 2520 34

Abstract: Both X-linked hypohidrotic ectodermal dysplasia (XLHED) and non-syndromic tooth agenesis (NSTA) result in symptoms of congenital tooth loss. This study investigated genetic causes in two families with XLHED and four families with NSTA. We screened for mutations of WNT10A, EDA, EDAR, EDARADD, PAX9, MSX1, AXIN2, LRP6, and WNT10B through Sanger sequencing. Whole exome sequencing was performed for the proband of NSTA Family 4. Novel mutation c.1051G>T (p.Val351Phe) and the known mutation c.467G>A (p.Arg156His) of Ectodysplasin A (EDA) were identified in families with XLHED. Novel EDA receptor (EDAR) mutation c.73C>T (p.Arg25*), known EDA mutation c.491A>C (p.Glu164Ala), and known Wnt family member 10A (WNT10A) mutations c.511C>T (p.Arg171Cys) and c.742C>T (p.Arg248*) were identified in families with NSTA. The novel EDA and EDAR mutations were predicted as being pathogenic through bioinformatics analyses and structural modeling. Two variants of WNT10A, c.374G>A (p.Arg125Lys) and c.125A>G (p.Asn42Ser), were found in patients with NSTA. The two WNT10A variants were predicted to affect the splicing of message RNA, but minigene experiments showed normal splicing of mutated minigenes. This study uncovered the genetic foundations with respect to six families with XLHED or NSTA. We identified six mutations, of which two were novel mutations of EDA and EDAR. This is the first report of a nonsense EDAR mutation leading to NSTA.
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PMID:Novel EDA or EDAR Mutations Identified in Patients with X-Linked Hypohidrotic Ectodermal Dysplasia or Non-Syndromic Tooth Agenesis. 2898 73