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Deep dental phenotyping and a novel FAM20A variant in patients with amelogenesis imperfecta type IG.Oral Diseases Sep 2023
PubMed: 37743631
DOI: 10.1111/odi.14751 -
Journal of Postgraduate Medicine 2024We report a 2.2 year-old-boy, born of consanguineous marriage, referred for short stature, with history of neonatal death and skeletal deformities in his older sibling....
We report a 2.2 year-old-boy, born of consanguineous marriage, referred for short stature, with history of neonatal death and skeletal deformities in his older sibling. Rhizo-mesomelic dwarfism was detected antenatally. Within 24 hours of birth, he developed multiple seizures. Examination revealed severe short stature, dolichocephaly, broad forehead, deep set eyes, low set ears, bulbous nose, small, irregular teeth, pointed chin, and triangular facies. He had rhizomelic shortening, stubby fingers, pes planus, and scanty hair. Neurological evaluation revealed ataxia, hypotonia, and global developmental delay. Skeletal survey radiograph revealed shallow acetabuli, short femurs and humerus, short, broad metacarpals and short cone-shaped phalanges with cupping of phalangeal bases. Clinical exome analysis revealed homozygous mutations involving the POC1A gene and the SLC13A5 gene responsible for SOFT syndrome and Kohlschutter-Tonz syndrome respectively, which were inherited from the parents. Both these syndromes are extremely rare, and their co-occurrence is being reported for the first time.
Topics: Male; Infant, Newborn; Humans; Child, Preschool; Epilepsy; Dementia; Amelogenesis Imperfecta; Abnormalities, Multiple; Osteochondrodysplasias; Dwarfism; Symporters; Cytoskeletal Proteins; Cell Cycle Proteins
PubMed: 37706418
DOI: 10.4103/jpgm.jpgm_1001_22 -
Frontiers in Oral Health 2023Enamel Renal Syndrome (ERS) (OMIM # 204690) is a rare genetic condition characterised by hypoplastic amelogenesis imperfecta, failed tooth eruption, intra-pulpal...
Enamel Renal Syndrome (ERS) (OMIM # 204690) is a rare genetic condition characterised by hypoplastic amelogenesis imperfecta, failed tooth eruption, intra-pulpal calcifications, gingival enlargement and occasionally nephrocalcinosis. In this case series, we report on four unrelated patients with a confirmed molecular diagnosis of ERS ( pathogenic variants) from Sub-Saharan Africa. The pathognomonic oral profile of ERS was mostly fulfilled in these patients, with the notable addition of an odontoma in one patient. The cases presented a spectrum of phenotypic severity both dentally and systemically. One patient presented with nephrocalcinosis and abnormal kidney function, one had reduced kidney size with normal kidney function, and two had no renal abnormalities. Patients presenting with the oral profile of ERS should receive a prompt referral to a nephrologist and a geneticist. They should receive long-term management from a multidisciplinary medical and dental team.
PubMed: 37675434
DOI: 10.3389/froh.2023.1228760 -
European Journal of Human Genetics :... Nov 2023Amelogenesis imperfecta (AI) is a group of rare genetic conditions characterized by quantitative and/or qualitative tooth enamel alterations. AI can manifest as an...
Amelogenesis imperfecta (AI) is a group of rare genetic conditions characterized by quantitative and/or qualitative tooth enamel alterations. AI can manifest as an isolated trait or as part of a syndrome. Recently, five biallelic disease-causing variants in the RELT gene were identified in 7 families with autosomal recessive amelogenesis imperfecta (ARAI). RELT encodes an orphan receptor in the tumor necrosis factor (TNFR) superfamily expressed during tooth development, with unknown function. Here, we report one Brazilian and two French families with ARAI and a distinctive hypomineralized phenotype with hypoplastic enamel, post-eruptive enamel loss, and occlusal attrition. Using Next Generation Sequencing (NGS), four novel RELT variants were identified (c.120+1G>A, p.(?); c.120+1G>T, p.(?); c.193T>C, p.(Cys65Arg) and c.1260_1263dup, p.(Arg422Glyfs*5)). Our findings extend the knowledge of ARAI dental phenotypes and expand the disease-causing variants spectrum of the RELT gene.
Topics: Humans; Amelogenesis Imperfecta; Receptors, Tumor Necrosis Factor; Phenotype; Brazil; Pedigree
PubMed: 37670079
DOI: 10.1038/s41431-023-01440-7 -
Intractable & Rare Diseases Research Aug 2023We performed a study to present a phenotypic and genotypic characterization of a patient clinically diagnosed with carbonic anhydrase II (CAII) deficiency syndrome....
We performed a study to present a phenotypic and genotypic characterization of a patient clinically diagnosed with carbonic anhydrase II (CAII) deficiency syndrome. Medical records were reviewed, and oral examination was performed. Sanger sequencing was undertaken for molecular diagnosis. The patient presented with osteopetrosis, renal tubular acidosis, cerebral calcification, blindness, deafness, and development delay. The oral manifestations included anterior open bite, posterior crossbite, tooth eruption impairment, and hypoplastic amelogenesis imperfecta (AI). Molecular analysis revealed a homozygous deletion (c.753delG, p.Asn252Thrfs*14) and confirmed the clinical diagnosis. This study suggests that AI can be another feature of CAII deficiency syndrome. For the first time, a disease-causing variant is reported to be associated with syndromic AI.
PubMed: 37662627
DOI: 10.5582/irdr.2023.01033 -
Zhonghua Kou Qiang Yi Xue Za Zhi =... Sep 2023FAM83H is one of the major pathogenic genes of amelogenesis imperfecta (AI). Previous studies focused on the abnormal enamel development and mineralization caused by...
FAM83H is one of the major pathogenic genes of amelogenesis imperfecta (AI). Previous studies focused on the abnormal enamel development and mineralization caused by the mutations in FAM83H. Here we aimed to observe other effects of FAM83H mutations on tooth eruption besides AI through clinical case analysis. Published AI cases with FAM83H mutations were searched through PubMed database, and the characteristics of tooth eruption of each cases were counted and analyzed. The literature search range was from January 1, 2008 to February 28, 2023, using the keywords FAM83H and amelogenesis imperfecta. The included literature must provide the detailed radiographic imaging or dental eruption information of AI patients, as well as FAM83H gene mutation information. The basic clinical information, tooth phenotypes, and mutations of all the enrolled cases were collected and analyzed in order to find the characteristics of abnormal tooth eruption. Among 45 papers about FAM83H related to AI, twenty meeting the inclusion criteria were selected, involving 50 AI patients carrying FAM83H mutations who had radiographic image data or the detailed description of tooth eruption. A total of 34 abnormal erupted teeth were from 12 patients (12/50, 24%), among which 85% (29/34) had clear eruption path without any eruption obstructions, either embedded (25/34, 74%) or partially erupted (4/34, 12%). Tooth position analysis found that abnormal eruption of canines and second molars accounted for the highest proportion, accounting for 38% (13/34) respectively. The mutations in FAM83H may lead to amelogenesis imperfecta as well as abnormal tooth eruption at specific tooth positions.
Topics: Humans; Amelogenesis Imperfecta; Tooth Eruption; Proteins; Dental Enamel; Mutation
PubMed: 37659852
DOI: 10.3760/cma.j.cn112144-20230318-00094 -
Clinical Dysmorphology Oct 2023
Topics: Humans; Amelogenesis Imperfecta; Dementia; Epilepsy; Mutation
PubMed: 37646740
DOI: 10.1097/MCD.0000000000000472 -
Clinical Oral Investigations Oct 2023The current research on single-nucleotide polymorphism (SNP) mutation sites at different positions of the FAM83H gene and their phenotypic changes leading to...
OBJECTIVES
The current research on single-nucleotide polymorphism (SNP) mutation sites at different positions of the FAM83H gene and their phenotypic changes leading to amelogenesis imperfecta (AI) is inconsistent. We identified a previously reported heterozygous nonsense mutation c.1192C>T (p.Q398*) in the FAM83H gene and conducted a comprehensive analysis of the dental ultrastructure and chemical composition changes induced by this mutation. Additionally, we predicted the protein feature affected by this mutation site. The aim was to further deepen our understanding of the diversity of AI caused by different mutation sites in the FAM83H gene.
METHODS
Whole-exome sequencing (WES) and Sanger sequencing were used to confirm the mutation sites. Physical features of the patient's teeth were investigated using various methods including cone beam computer tomography (CBCT), scanning electron microscopy (SEM), contact profilometry (roughness measurement), and a nanomechanical tester (nanoindentation measurement). The protein features of wild-type and mutant FAM83H were predicted using bioinformatics methods.
RESULTS
One previously discovered FAM83H heterozygous nonsense mutation c.1192C>T (p.Q398*) was detected in the patient. SEM revealed inconsistent dentinal tubules, and EDS showed that calcium and phosphorus were lower in the patient's dentin but higher in the enamel compared to the control tooth. Roughness measurements showed that AI patients' teeth had rougher occlusal surfaces than those of the control tooth. Nanoindentation measurements showed that the enamel and dentin hardness values of the AI patients' teeth were both significantly reduced compared to those of the control tooth. Compared to the wild-type FAM83H protein, the mutant FAM83H protein shows alterations in stability, hydrophobicity, secondary structure, and tertiary structure. These changes could underlie functional differences and AI phenotype variations caused by this mutation site.
CONCLUSIONS
This study expands the understanding of the effects of FAM83H mutations on tooth structure.
CLINICAL RELEVANCE
Our study enhances our understanding of the genetic basis of AI and may contribute to improved diagnostics and personalized treatment strategies for patients with FAM83H-related AI.
Topics: Humans; Amelogenesis Imperfecta; Codon, Nonsense; Dental Enamel; Proteins; Mutation
PubMed: 37615776
DOI: 10.1007/s00784-023-05228-3 -
Developmental Cell Oct 2023Tooth enamel secreted by ameloblasts (AMs) is the hardest material in the human body, acting as a shield to protect the teeth. However, the enamel is gradually damaged...
Tooth enamel secreted by ameloblasts (AMs) is the hardest material in the human body, acting as a shield to protect the teeth. However, the enamel is gradually damaged or partially lost in over 90% of adults and cannot be regenerated due to a lack of ameloblasts in erupted teeth. Here, we use single-cell combinatorial indexing RNA sequencing (sci-RNA-seq) to establish a spatiotemporal single-cell census for the developing human tooth and identify regulatory mechanisms controlling the differentiation process of human ameloblasts. We identify key signaling pathways involved between the support cells and ameloblasts during fetal development and recapitulate those findings in human ameloblast in vitro differentiation from induced pluripotent stem cells (iPSCs). We furthermore develop a disease model of amelogenesis imperfecta in a three-dimensional (3D) organoid system and show AM maturation to mineralized structure in vivo. These studies pave the way for future regenerative dentistry.
Topics: Humans; Ameloblasts; Amelogenesis; Dental Enamel; Odontogenesis; Tooth
PubMed: 37582367
DOI: 10.1016/j.devcel.2023.07.013 -
Journal of Dental Research Oct 2023Amelogenin plays a crucial role in tooth enamel formation, and mutations on X-chromosomal amelogenin cause X-linked amelogenesis imperfecta (AI). Amelogenin...
Amelogenin plays a crucial role in tooth enamel formation, and mutations on X-chromosomal amelogenin cause X-linked amelogenesis imperfecta (AI). Amelogenin pre-messenger RNA (mRNA) is highly alternatively spliced, and during alternative splicing, exon4 is mostly skipped, leading to the formation of a microRNA (miR-exon4) that has been suggested to function in enamel and bone formation. While delivering the functional variation of amelogenin proteins, alternative splicing of exon4 is the decisive first step to producing miR-exon4. However, the factors that regulate the splicing of exon4 are not well understood. This study aimed to investigate the association between known mutations in exon4 and exon5 of X chromosome amelogenin that causes X-linked AI, the splicing of exon4, and miR-exon4 formation. Our results showed mutations in exon4 and exon5 of the amelogenin gene, including c.120T>C, c.152C>T, c.155C>G, and c.155delC, significantly affected the splicing of exon4 and subsequent miR-exon4 production. Using an amelogenin minigene transfected in HEK-293 cells, we observed increased inclusion of exon4 in amelogenin mRNA and reduced miR-exon4 production with these mutations. In silico analysis predicted that Ser/Arg-rich RNA splicing factor (SRSF) 2 and SRSF5 were the regulatory factors for exon4 and exon5 splicing, respectively. Electrophoretic mobility shift assay confirmed that SRSF2 binds to exon4 and SRSF5 binds to exon5, and mutations in each exon can alter SRSF binding. Transfection of the amelogenin minigene to LS8 ameloblastic cells suppressed expression of the known miR-exon4 direct targets, and , related to multiple pathways. Given the mutations on the minigene, the expression of has been significantly upregulated with c.155C>G and c.155delC mutations. Together, we confirmed that exon4 splicing is critical for miR-exon4 production, and mutations causing X-linked AI in exon4 and exon5 significantly affect exon4 splicing and following miR-exon4 production. The change in miR-exon4 would be an additional etiology of enamel defects seen in some X-linked AI.
Topics: Humans; Amelogenin; Amelogenesis Imperfecta; HEK293 Cells; Mutation; Dental Enamel Proteins; MicroRNAs; RNA, Messenger
PubMed: 37563801
DOI: 10.1177/00220345231180572