PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis

Macchia, Paolo Emidio; Lapi, Paola; Krude, Heiko; Mt, Pirro; Missero, Caterina; Chiovato, Luca; Souabni, Abdallah; Baserga, Mariangiola; Tassi, Valentina; Pinchera, Aldo; Fenzi, Gianfranco; Grüters, Annette; Busslinger, Meinrad; Lauro, Roberto Di

doi:10.1038/ng0598-83

Cited by 446 publications

(305 citation statements)

References 17 publications

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“…The arginine is mutated to leucine in PAX3 in one family with Waardenburg's syndrome type 1, 17 in PAX6 to glycine in a family with anterior segment abnormalities of the eye, 18 and in PAX8 to histidine in one patient with hypoplasia of the thyroid gland. 19 This far, four different PAX9 mutations have been reported in families affected with severe lack of permanent teeth, in particular of permanent molars and premolars. Characteristically, when a premolar or molar tooth is missing, all the posterior teeth on the same hemiarch are also absent.…”

Section: Discussionmentioning

confidence: 99%

A missense mutation in PAX9 in a family with distinct phenotype of oligodontia

et al. 2003

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Mutations in PAX9 have been described for families in which inherited oligodontia characteristically involves permanent molars. Our study analysed one large family with dominantly inherited oligodontia clinically and genetically. In addition to permanent molars, some teeth were congenitally missing in the premolar, canine, and incisor regions. Measurements of tooth size revealed the reduced size of the proband's and his father's deciduous and permanent teeth. This phenotype is distinct from oligodontia phenotypes associated with mutations in PAX9. Sequencing of the PAX9 gene revealed a missense mutation in the beginning of the paired domain of the molecule, an arginine-to-tryptophan amino-acid change occurring in a position absolutely conserved in all sequenced paired box genes. A mutation of the homologous arginine of PAX6 has been shown to affect the target DNA specificity of PAX6. We suggest that a similar mechanism explains these distinct oligodontia phenotypes.

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Section: Discussionmentioning

confidence: 99%

A missense mutation in PAX9 in a family with distinct phenotype of oligodontia

et al. 2003

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“…Disruption of at least five PAX genes has been shown to result in developmental abnormalities in humans. [1][2][3][4][5][6][7] So far, eight different PAX2 mutations have been reported in 13 patients with RCS. [7][8][9][10][11][12][13] In all previously reported cases, patients presented with RCS or renal hypoplasia with mild ocular manifestations described as optic disc dysplasia or papillo-renal syndrome.…”

Section: Discussionmentioning

confidence: 99%

PAX2 mutations in renal–coloboma syndrome: mutational hotspot and germline mosaicism

et al. 2000

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The renal-coloboma syndrome (RCS, MIM 120330) is an autosomal dominant disorder caused by PAX2 gene mutations. We screened the entire coding sequence of the PAX2 gene for mutations in nine patients with RCS. We found five heterozygous PAX2 gene mutations: a dinucleotide insertion (2G) at position 619 in one sporadic RCS case, a single nucleotide insertion (619 + G) in three unrelated cases, and a single nucleotide deletion in a familial case. In this familial case, three affected sibs showed a striking ocular phenotypic variability. Each of the sibs carried a 619insG mutation, whilst unaffected parents did not, suggesting the presence of germline mosaicism. Interestingly, the 619insG mutation has been previously reported in several patients and is also responsible for the Pax2 1Neu mouse mutant, an animal model of human RCS. This study confirms the critical role of the PAX2 gene in human renal and ocular development. In addition, it emphasises the high variability of ocular defects associated with PAX2 mutations ranging from subtle optic disc anomalies to microphthalmia. Finally, the presence of PAX2 germline mosaicism highlights the difficulties associated with genetic counselling for PAX2 mutations. European Journal of Human Genetics (2000) 8, 820-826.

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“…12,23 -29 These coding regions were amplified with primers reported previously. 12,27 For the NKX2.1 analysis, the entire coding region was amplified with primers flanking the three exons of the gene (PCR conditions and sequences of the primers will be supplied upon request). For the TSHR gene, the 10 exons were amplified and directly sequenced as described previously.…”

Section: Mutational Analysismentioning

confidence: 99%

Linkage and mutational analysis of familial thyroid dysgenesis demonstrate genetic heterogeneity implicating novel genes

et al. 2004

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The pathophysiology of thyroid dysgenesis (TD) is not elucidated yet in the majority of cases. The unexpected familial clustering of congenital hypothyroidism due to TD suggests a genetically determined disorder. Four genes have been hitherto involved in thyroid development, including migration and growth. Three of these encode transcription factors (the thyroid transcription factors 1 and 2 (TTF1 or NKX2.1 and TTF2 or FOXE1) and PAX8) while the other encodes the thyrotropin hormone receptor (TSHR). Some mutations have been reported in patients affected by thyroid defects, which supports the relevance of these four genes in TD. However, their involvement in the general TD population remains questionable. Therefore, to document their involvement, we performed a linkage analysis followed by mutational analysis in 19 multiplex TD families. The LOD score results failed to prove linkage between any of the four genes and the TD phenotype, whatever the postulated mode of inheritance. Manual extended haplotypes showed allele sharing among affected individuals of at least one of these four genes in the majority of families. Nevertheless, mutational analysis did not identify mutations in these cases, arguing in favor of identity by descent and not identity by state. Furthermore, as a main result of the present study, extended haplotypes confirmed by mutational analysis showed that the four genes were excluded in five out of the 19 investigated families, demonstrating the relevance of other genes. In conclusion, the present study demonstrates genetic heterogeneity in the TD disorder and suggests the involvement of novel genes.

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PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis

Cited by 446 publications

References 17 publications

A missense mutation in PAX9 in a family with distinct phenotype of oligodontia

A missense mutation in PAX9 in a family with distinct phenotype of oligodontia

PAX2 mutations in renal–coloboma syndrome: mutational hotspot and germline mosaicism

Linkage and mutational analysis of familial thyroid dysgenesis demonstrate genetic heterogeneity implicating novel genes

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