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BMC Oral Health Nov 2023Amelogenesis imperfecta (AI) is a developmental enamel defect affecting the structure of enamel, esthetic appearance, and the tooth masticatory function. Gene mutations...
BACKGROUND
Amelogenesis imperfecta (AI) is a developmental enamel defect affecting the structure of enamel, esthetic appearance, and the tooth masticatory function. Gene mutations are reported to be relevant to AI. However, the mechanism underlying AI caused by different mutations is still unclear. This study aimed to reveal the molecular pathogenesis in AI families with 2 novel pre-mRNA splicing mutations.
METHODS
Two Chinese families with AI were recruited. Whole-exome sequencing and Sanger sequencing were performed to identify mutations in candidate genes. Minigene splicing assays were performed to analyze the mutation effects on mRNA splicing alteration. Furthermore, three-dimensional structures of mutant proteins were predicted by AlphaFold2 to evaluate the detrimental effect.
RESULTS
The affected enamel in family 1 was thin, rough, and stained, which was diagnosed as hypoplastic-hypomature AI. Genomic analysis revealed a novel splicing mutation (NM_001142.2: c.570 + 1G > A) in the intron 6 of amelogenin (AMELX) gene in family 1, resulting in a partial intron 6 retention effect. The proband in family 2 exhibited a typical hypoplastic AI, and the splicing mutation (NM_031889.2: c.123 + 4 A > G) in the intron 4 of enamelin (ENAM) gene was observed in the proband and her father. This mutation led to exon 4 skipping. The predicted structures showed that there were obvious differences in the mutation proteins compared with wild type, leading to impaired function of mutant proteins.
CONCLUSIONS
In this study, we identified two new splicing mutations in AMELX and ENAM genes, which cause hypoplastic-hypomature and hypoplastic AI, respectively. These results expand the spectrum of genes causing AI and broaden our understanding of molecular genetic pathology of enamel formation.
Topics: Humans; Female; Amelogenin; Amelogenesis Imperfecta; Dental Enamel Proteins; Mutation; Mutant Proteins; Extracellular Matrix Proteins
PubMed: 37985977
DOI: 10.1186/s12903-023-03508-8 -
Journal of Medical Genetics Mar 2024Collagen XVII is most typically associated with human disease when biallelic variants (>230) cause junctional epidermolysis bullosa (JEB), a rare, genetically...
BACKGROUND
Collagen XVII is most typically associated with human disease when biallelic variants (>230) cause junctional epidermolysis bullosa (JEB), a rare, genetically heterogeneous, mucocutaneous blistering disease with amelogenesis imperfecta (AI), a developmental enamel defect. Despite recognition that heterozygous carriers in JEB families can have AI, and that heterozygous variants also cause dominant corneal epithelial recurrent erosion dystrophy (ERED), the importance of heterozygous variants causing dominant non-syndromic AI is not widely recognised.
METHODS
Probands from an AI cohort were screened by single molecule molecular inversion probes or targeted hybridisation capture (both a custom panel and whole exome sequencing) for variants. Patient phenotypes were assessed by clinical examination and analyses of affected teeth.
RESULTS
Nineteen unrelated probands with isolated AI (no co-segregating features) had 17 heterozygous, potentially pathogenic variants, including missense, premature termination codons, frameshift and splice site variants in both the endo-domains and the ecto-domains of the protein. The AI phenotype was consistent with enamel of near normal thickness and variable focal hypoplasia with surface irregularities including pitting.
CONCLUSION
These results indicate that variants are a frequent cause of dominantly inherited non-syndromic AI. Comparison of variants implicated in AI and JEB identifies similarities in type and distribution, with five identified in both conditions, one of which may also cause ERED. Increased availability of genetic testing means that more individuals will receive reports of heterozygous variants. We propose that patients with isolated AI or ERED, due to variants, should be considered as potential carriers for JEB and counselled accordingly, reflecting the importance of multidisciplinary care.
Topics: Humans; Non-Fibrillar Collagens; Autoantigens; Amelogenesis Imperfecta; Heterozygote; Phenotype; Mutation
PubMed: 37979963
DOI: 10.1136/jmg-2023-109510 -
BMC Medical Genomics Nov 2023This study reported the first case of Kohlschütter-Tönz syndrome (KTS) in China and reviewed the literature of the reported cases. (Review)
Review
PURPOSE
This study reported the first case of Kohlschütter-Tönz syndrome (KTS) in China and reviewed the literature of the reported cases.
METHODS
This patient was registered at the Children's Hospital of Chongqing Medical University. The patient's symptoms and treatments were recorded in detail, and the patient was monitored for six years. We employed a combination of the following search terms and Boolean operators in our search strategy: Kohlschütter-Tönz syndrome, KTS, and ROGDI. These terms were carefully selected to capture a broad range of relevant publications in PubMed, Web of Science, WHO Global Health Library, and China National Knowledge Infrastructure, including synonyms, variations, and specific terms related to KTS. The pathogenicity of the variants was predicted using SpliceAI and MutationTaster, and the structures of the ROGDI mutations were constructed using I-TASSER.
RESULTS
This is the first case report of KTS in China. Our patient presented with epilepsy, global developmental delay, and amelogenesis imperfecta. A trio-WES revealed homozygous mutations in ROGDI (c.46-37_46-30del). The brain magnetic resonance imaging (MRI) and video electroencephalogram (VEEG) were normal. The efficacy of perampanel (PMP) in treating seizures and intellectual disability was apparent. Furthermore, 43 cases of ROGDI-related KTS were retrieved. 100% exhibited epilepsy, global developmental delay, and amelogenesis imperfecta. 17.2% received a diagnosis of attention deficit hyperactivity disorder (ADHD), and 3.4% were under suspicion of autism spectrum disorder (ASD). Language disorders were observed in all patients. Emotional disorders, notably self-harm behaviors (9.1%), were also reported.
CONCLUSION
ROGDI-related KTS is a rare neurodegenerative disorder, characterized by three classic clinical manifestations: epilepsy, global developmental delay, and amelogenesis imperfecta. Moreover, patients could present comorbidities, including ADHD, ASD, emotional disorders, and language disorders. PMP may be a potential drug with relatively good efficacy, but long-term clinical trials are still needed.
Topics: Child; Humans; Amelogenesis Imperfecta; Autism Spectrum Disorder; Epilepsy; Language Disorders; Membrane Proteins; Nuclear Proteins
PubMed: 37974187
DOI: 10.1186/s12920-023-01728-z -
Journal of Personalized Medicine Oct 2023Hereditary conditions that affect tooth enamel in quantity and/or quality are called amelogenesis imperfecta (AI). AI can occur as an isolated condition or as a symptom...
Hereditary conditions that affect tooth enamel in quantity and/or quality are called amelogenesis imperfecta (AI). AI can occur as an isolated condition or as a symptom of a syndrome. An OMIM search with the term "AI" yielded 79 result entries. Mutations in the same gene cause syndromic or non-syndromic AI, depending on the nature of the mutations. In this study, we recruited two AI families and performed mutational analysis using whole-exome sequencing. The proband of family 1, with hypoplastic pitted AI and mild localized atopic dermatitis, had compound heterozygous mutations (paternal NM_000494.4: c.3598G>T, p.Asp1200Tyr and maternal c.1700G>A, p.Gly567Glu). The proband of family 2, with hypoplastic pitted AI and Jervell and Lange-Nielsen syndrome, had a recurrent mutation (NM_000228.3: c.3463_3475del, p.(Glu1155Thrfs*51)) in addition to compound heterozygous mutations in the KCNQ1 gene.
PubMed: 37888105
DOI: 10.3390/jpm13101494 -
Journal of Medical Case Reports Oct 2023Metabolic bone disease causes significant morbidity and mortality, especially when misdiagnosed. With genetic testing, multiple disease pathologies can be analyzed.
BACKGROUND
Metabolic bone disease causes significant morbidity and mortality, especially when misdiagnosed. With genetic testing, multiple disease pathologies can be analyzed.
CASE PRESENTATION
A 5-year and 9-month-old otherwise healthy Yemeni girl presented to her Yemen physician for evaluation of inward bending of her right knee and short stature. After extensive medical testing, she was given a diagnosis of hypophosphatemic rickets and growth hormone deficiency and started on treatment. Despite appropriate treatment, however, her condition continued to progress, prompting her family to pursue additional workup including genetic testing outside of Yemen. Genetic testing ultimately revealed a variation of unknown significance associated with amelogenesis imperfecta.
CONCLUSIONS
Hypophosphatemic rickets secondary to renal tubular acidosis was the working diagnosis. However, the patient's condition did not improve. Further genetic testing revealed a variation of unknown significance associated with amelogenesis imperfecta. We aim to present this case, provide an overview of the causes, and diagnostic metabolic bone health evaluation.
Topics: Female; Humans; Infant; Amelogenesis Imperfecta; Rickets, Hypophosphatemic; Acidosis, Renal Tubular; Diagnostic Errors
PubMed: 37858137
DOI: 10.1186/s13256-023-04164-w -
The Journal of Clinical Pediatric... Sep 2023The term Molar-Incisor Hypomineralisation (MIH) is used to describe hypomineralised defects of systemic origin that affect at least one of the first permanent molars and...
The term Molar-Incisor Hypomineralisation (MIH) is used to describe hypomineralised defects of systemic origin that affect at least one of the first permanent molars and often involves the permanent incisors. Antibiotic therapy during amelogenesis may be associated with enamel hypomineralisation. By examining children with Sickle Cell Disease (SCD), who take prophylactic antibiotics daily from birth until age five, it may be possible to determine if there is an increased prevalence of MIH in this population. The aim of this study was to determine the effect of long-term antibiotic use on the prevalence and severity of MIH in children with SCD. In a prospective cohort pilot study over a period of seven months, children aged 7-17 years, with SCD at Boston Children's Hospital (n = 18) were examined for MIH. Information regarding peri-natal concerns, incidence of illness and antibiotic use were also collected. The results were compared to a group of control patients (n = 63) for prevalence and severity of MIH using Fisher's exact test. The patients with SCD, 4/18 (22%) taking daily antibiotics did not show a statistically significant greater prevalence of MIH compared to the control group, 24/63 (38%). There was no correlation between MIH and pneumonia, asthma, fever, flu, otitis media, breastfeeding, gender and birth weight. However, an association was noted between premature birth and MIH ( ≤ 0.05). No correlation was found between long-term antibiotic use and higher prevalence of MIH in the SCD group compared to the control group. However, MIH may be more severe in those with a history of long-term antibiotics.
Topics: Child; Female; Pregnancy; Humans; Pilot Projects; Molar Hypomineralization; Prospective Studies; Anemia, Sickle Cell; Anti-Bacterial Agents; Molar
PubMed: 37732434
DOI: 10.22514/jocpd.2023.052 -
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 -
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 -
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