Distal renal tubular acidosis, autoimmune thyroiditis, enamel hypomaturation, and tooth agenesis caused by homozygosity of a novel double-nucleotide substitution in SLC4A4

Kantaputra, Piranit Nik; Güven, Yeliz; Aksu, Bağdagül; Kalaycı, Tuğba; Doğan, Cezmi; Intachai, Worrachet; Olsen, Bjørn R.; Tongsima, Sissades; Ngamphiw, Chumpol; Noppakun, Kajohnsak

doi:10.1016/j.adaj.2021.12.009

Cited by 6 publications

(5 citation statements)

References 33 publications

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“…Finally, we believe that the mutations we found in LRP5 and BMP4 were associated with dental anomalies because whole exome sequencing in all patients did not reveal rare variants in other known tooth‐associated genes, including WNT10A , WNT10B , AXIN2 , PAX9 , MSX1 , LRP6 , GREM2 , TSPEAR , TFAP2B , LAMB3 , PITX2 , EDA , EDAR , EDARADD , EVC , EVC2 , COL1A2 , ANTXR1 , CREBBP , FGF10 , SMOC2 , KREMEN1 , and KDF1 11 …”

Section: Discussionmentioning

confidence: 84%

Mutations in LRP5 and BMP4 are associated with mesiodens, tooth agenesis, root malformation, and oral exostoses

et al. 2022

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WNT/β-catenin and BMP signaling pathways play important roles in the process of tooth development. Dysregulation of WNT/β-catenin and BMP signaling is implicated in a number of human malformations, including dental anomalies.Whole exome and Sanger sequencing identified seven patients with LRP5 mutations (p. Asn1121Asp, p.Asp856Asn, p.Val1433Met, and p.Val1245Met) and six patients with BMP4 mutations (p.Asn150Lys, p.Gly168Arg, p.Arg269Gln, and p.Ala42Glu). All patients were affected with isolated dental anomalies (dental anomalies with no other structural defects), including mesiodens, tooth agenesis, unseparated roots, narrow roots, shortened and tapered roots, and taurodontism.Five patients with LRP5 and one with BMP4 mutations had oral exostoses. Protein models of LRP5 mutations indicate the possible functional effects of the mutations. Here we report for the first time that mutations in LRP5 are associated with dental anomalies. LRP5 appears to be the first gene related to pathogenesis of mesiodens. We also show for the first time that in addition to tooth agenesis, mutations in BMP4 are also implicated in root maldevelopment and torus mandibularis. Sharing of the phenotypes of the patients with LRP5 and BMP4 mutations, which include root maldevelopment, tooth agenesis, and torus mandibularis, implicates cross talks between the WNT/β-catenin and BMP signaling pathways, especially during root development.

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Section: Discussionmentioning

confidence: 84%

Mutations in LRP5 and BMP4 are associated with mesiodens, tooth agenesis, root malformation, and oral exostoses

et al. 2022

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“…It is hypothesized that the LRP4 mutations we found were associated with dental anomalies, because the analysis of exome sequencing in the patients did not show rare variants in other known tooth‐related genes, including WNT10A , WNT10B , PAX9 , AXIN2 , MSX1 , LRP6 , BMP4 , GREM2 , TFAP2B , TSPEAR , LAMB3 , EDA , EDAR , EDARADD , PITX2 , EVC , EVC2 , COL1A2 , ANTXR1 , CREBBP , FGF10 , SMOC2 , KREMEN1 , KDF1 , and WLS 15,33 …”

Section: Discussionmentioning

confidence: 92%

“…13,31,32 It is hypothesized that the LRP4 mutations we found were associated with dental anomalies, because the analysis of exome sequencing in the patients did not show rare variants in other known tooth-related genes, including WNT10A, WNT10B, PAX9, AXIN2, MSX1, LRP6, BMP4, GREM2, TFAP2B, TSPEAR, LAMB3, EDA, EDAR, EDARADD, PITX2, EVC, EVC2, COL1A2, ANTXR1, CREBBP, FGF10, SMOC2, KREMEN1, KDF1, and WLS. 15,33 Patient 4, who had the heterozygous variant p.Ar-g263His in LRP4, also carried a de novo nonsense mutation c.3523C>T; p.Arg1175Ter in LRP6 (Table 1; Figure S1). This LRP6 variant is not reported in public databases, including gnomAD and LOVD; therefore, it is considered novel.…”

Section: Discussionmentioning

confidence: 99%

LRP4 mutations, dental anomalies, and oral exostoses

Kantaputra,

Panichkul,

Sillapasorn

et al. 2023

Int J Paed Dentistry

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BackgroundIn order to generate a normal set of teeth, fine‐tuning of Wnt/β‐catenin signaling is required, in which WNT ligands bind to their inhibitors or WNT inhibitors bind to their co‐receptors. Lrp4 regulates the number of teeth and their morphology by modulating Wnt/β‐catenin signaling as a Wnt/β‐catenin activator or inhibitor, depending on its interactions with the partner proteins, such as Sostdc1 and Dkk1.AimTo investigate genetic etiologies of dental anomalies involving LRP4 in a Thai cohort of 250 children and adults with dental anomalies.DesignOral and radiographic examinations and whole exome sequencing were performed for every patient.ResultsTwo novel (p.Leu1356Arg and p.Ala1702Gly) and three recurrent (p.Arg263His, p.Gly1314Ser, and p.Asn1385Ser) rare variants in low‐density lipoprotein receptor‐related protein 4 (LRP4: MIM 604270) were identified in 11 patients. Oral exostoses were observed in five patients.ConclusionAntagonism of Bmp signaling by Sostdc1 requires the presence of Lrp4. Mice lacking Lrp4 have been demonstrated to have alteration of Wnt–Bmp–Shh signaling and an abnormal number of incisors. Therefore, the LRP4 mutations found in our patients may disrupt Wnt–Bmp–Shh signaling, thereby resulting in dental anomalies and oral exostoses. Root maldevelopment in the patients suggests an important role of LRP4 in root morphogenesis.

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“…Proximal RTA with ocular abnormalities (OMIM phenotype number 604278 ) is an AR condition associated with impaired intellectual development, and rarely NL and NC ( Guo et al, 2023 ). Distal RTA, autoimmune thyroiditis, tooth agenesis, enamel hypomaturation, and pulp stones is an AR condition with only 1 case reported with the only case being associated with NC and NL ( Kantaputra et al, 2022 ).…”

Section: Genetic Causes Of Nephrolithiasis and Nephrocalcinosis In Ch...mentioning

confidence: 99%

Review of childhood genetic nephrolithiasis and nephrocalcinosis

Gefen,

Zaritsky

2024

Front. Genet.

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Nephrolithiasis (NL) is a common condition worldwide. The incidence of NL and nephrocalcinosis (NC) has been increasing, along with their associated morbidity and economic burden. The etiology of NL and NC is multifactorial and includes both environmental components and genetic components, with multiple studies showing high heritability. Causative gene variants have been detected in up to 32% of children with NL and NC. Children with NL and NC are genotypically heterogenous, but often phenotypically relatively homogenous, and there are subsequently little data on the predictors of genetic childhood NL and NC. Most genetic diseases associated with NL and NC are secondary to hypercalciuria, including those secondary to hypercalcemia, renal phosphate wasting, renal magnesium wasting, distal renal tubular acidosis (RTA), proximal tubulopathies, mixed or variable tubulopathies, Bartter syndrome, hyperaldosteronism and pseudohyperaldosteronism, and hyperparathyroidism and hypoparathyroidism. The remaining minority of genetic diseases associated with NL and NC are secondary to hyperoxaluria, cystinuria, hyperuricosuria, xanthinuria, other metabolic disorders, and multifactorial etiologies. Genome-wide association studies (GWAS) in adults have identified multiple polygenic traits associated with NL and NC, often involving genes that are involved in calcium, phosphorus, magnesium, and vitamin D homeostasis. Compared to adults, there is a relative paucity of studies in children with NL and NC. This review aims to focus on the genetic component of NL and NC in children.

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Distal renal tubular acidosis, autoimmune thyroiditis, enamel hypomaturation, and tooth agenesis caused by homozygosity of a novel double-nucleotide substitution in SLC4A4

Cited by 6 publications

References 33 publications

Mutations in LRP5 and BMP4 are associated with mesiodens, tooth agenesis, root malformation, and oral exostoses

Mutations in LRP5 and BMP4 are associated with mesiodens, tooth agenesis, root malformation, and oral exostoses

LRP4 mutations, dental anomalies, and oral exostoses

Review of childhood genetic nephrolithiasis and nephrocalcinosis

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