Molecular‐based phenotype variations in amelogenesis imperfecta

Dong, Jing; Ruan, Wenyan; Duan, Xiaohong

doi:10.1111/odi.14599

Cited by 9 publications

(3 citation statements)

References 315 publications

(425 reference statements)

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“…AI is a heterogeneous group of genetic conditions characterised by a deficit in enamel quantity and/or quality affecting all teeth of both dentitions. [42][43][44] It can present as an isolated disease or can be part of more complex and diverse syndromes affecting other tissues and organs. Once formed and following tooth eruption, enamel has no capacity for cellular repair.…”

Section: Novel Disease Locimentioning

confidence: 99%

Biallelic variants in Plexin B2 ( PLXNB2 ) cause amelogenesis imperfecta, hearing loss and intellectual disability

Smith,

Laugel-Haushalter,

Hany

et al. 2024

J Med Genet

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BackgroundPlexins are large transmembrane receptors for the semaphorin family of signalling proteins. Semaphorin-plexin signalling controls cellular interactions that are critical during development as well as in adult life stages. Nine plexin genes have been identified in humans, but despite the apparent importance of plexins in development, only biallelicPLXND1andPLXNA1variants have so far been associated with Mendelian genetic disease.MethodsEight individuals from six families presented with a recessively inherited variable clinical condition, with core features of amelogenesis imperfecta (AI) and sensorineural hearing loss (SNHL), with variable intellectual disability. Probands were investigated by exome or genome sequencing. Common variants and those unlikely to affect function were excluded. Variants consistent with autosomal recessive inheritance were prioritised. Variant segregation analysis was performed by Sanger sequencing. RNA expression analysis was conducted in C57Bl6 mice.ResultsRare biallelic pathogenic variants in plexin B2 (PLXNB2), a large transmembrane semaphorin receptor protein, were found to segregate with disease in all six families. The variants identified include missense, nonsense, splicing changes and a multiexon deletion.Plxnb2expression was detected in differentiating ameloblasts.ConclusionWe identify rare biallelic pathogenic variants inPLXNB2as a cause of a new autosomal recessive, phenotypically diverse syndrome with AI and SNHL as core features. Intellectual disability, ocular disease, ear developmental abnormalities and lymphoedema were also present in multiple cases. The variable syndromic human phenotype overlaps with that seen inPlxnb2knockout mice, and, together with the rarity of humanPLXNB2variants, may explain why pathogenic variants inPLXNB2have not been reported previously.

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Section: Novel Disease Locimentioning

confidence: 99%

Biallelic variants in Plexin B2 ( PLXNB2 ) cause amelogenesis imperfecta, hearing loss and intellectual disability

Smith,

Laugel-Haushalter,

Hany

et al. 2024

J Med Genet

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“…Furthermore, in the past, AI used to be classified only as an isolated trait caused by variants in genes that encoded for enamel matrix proteins or proteases. Advances in molecular diagnosis techniques have identified disease-causing variants in at least 26 different genes that cause 19 types of syndromic AI (9), including five autosomal recessive renal diseases linked to CLDN16 (#OMIM 248250), CLDN19 (#OMIM 248190), FAM20A (#OMIM 204690), KCNJ1 (#OMIM 241200) and SLC4A4 genes (#OMIM 604278). All these…”

Section: Wwwirdrjournalcommentioning

confidence: 99%

“…Amelogenesis imperfecta (AI) comprises a heterogeneous group of inherited development defects of enamel (DDE) (9). AI can be an isolated or syndromic trait that affects all or almost all teeth in both dentitions.…”

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confidence: 99%

Carbonic anhydrase II deficiency syndrome with amelogenesis imperfecta linked to a homozygous <i>CA2</i> deletion

Leite,

Resende,

Rosa

et al. 2023

IRDR

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amelogenesis imperfecta, osteopetrosis, renal tubular acidosis, carbonic anhydrase II 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 CA2 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 CA2 disease-causing variant is reported to be associated with syndromic AI.

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KDF1 promotes ameloblast differentiation by inhibiting the IKK/IκB/NF‐κB axis

Liu,

Yu,

Sun

et al. 2024

Journal Cellular Physiology

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Enamel protects teeth from external irritation and its formation involves sequential differentiation of ameloblasts, a dental epithelial cell. Keratinocyte differentiation factor 1 (KDF1) is important in the development of epithelial tissues and organs. However, the specific role of KDF1 in enamel formation and corresponding regulatory mechanisms are unclear. This study demonstrated that KDF1 was persistently expressed in all stages of ameloblast differentiation, through RNAscope in situ hybridization. KDF1 expression in the mouse ameloblast cell line LS8 was demonstrated via immunofluorescence assay. KDF1 was knocked out in LS8 cells using the CRISPR/Cas‐9 system or overexpressed in LS8 cells through lentiviral infection. In vitro ameloblast differentiation induction, quantitative reverse transcription PCR, western blot analysis, and alkaline phosphatase (ALP) assay indicated that knockout or overexpression of KDF1 in LS8 cells decreased or increased the mRNA and protein levels of several key amelogenesis markers, as well as ALP activity. Furthermore, liquid chromatography‐mass spectrometry and co‐immunoprecipitation analyses revealed that KDF1 can interact with the IKK complex, thereby inhibiting the NF‐κB pathway. Suppressing NF‐κB activity partially recovered the decreased ameloblast differentiation in LS8 cells induced by KDF1‐knockout. This study demonstrated that KDF1 can promote ameloblast differentiation of LS8 cells by inhibiting the IKK/IκB/NF‐κB axis, and is a potential target for functional enamel regeneration.

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Molecular‐based phenotype variations in amelogenesis imperfecta

Cited by 9 publications

References 315 publications

Biallelic variants in Plexin B2 ( PLXNB2 ) cause amelogenesis imperfecta, hearing loss and intellectual disability

Biallelic variants in Plexin B2 ( PLXNB2 ) cause amelogenesis imperfecta, hearing loss and intellectual disability

Carbonic anhydrase II deficiency syndrome with amelogenesis imperfecta linked to a homozygous <i>CA2</i> deletion

KDF1 promotes ameloblast differentiation by inhibiting the IKK/IκB/NF‐κB axis

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