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Purpose: The CDC73 gene, encoding parafibromin, has been identified as a tumour suppressor gene both in hyperparathyroidism-jaw tumour (HPT-JT) syndrome and in sporadic parathyroid carcinoma. While the vast majority of CDC73 mutations affect the N-terminus or the central core of the encoded protein, as yet few mutations have been reported affecting the C-terminus. Here, we report a case (Caucasian female, 28 years) with an invasive ossifying fibroma of the left mandible and hyperparathyroidism (sCa = 16 mg/dl, PTH = 660 pg/mL) due to a parathyroid lesion of 20 mm, hystologically diagnosed as carcinoma. Methods: The whole CDC73 gene was screened for the presence of mutations by Sanger sequencing. Immunohistochemistry, in vitro functional assays, Western blotting, MTT assays and in-silico modelling were performed to assess the effect of the detected mutation. Results: Sequence analysis of the CDC73 gene in the proband revealed the presence of a novel deletion affecting the C-terminus of the encoded protein (c.1379delT/p.L460Lfs*18). Clinical and genetic analyses of the available relatives led to the identification of three additional carriers, one of whom was also affected by a parathyroid lesion. Immunohistochemistry, Western blotting, MTT and in-silico modelling assays revealed that the deletion leads to down-regulation of the mutated protein, most likely through a proteasome-mediated pathway. We also found that the deletion may cause a conformational change in the C-terminus of the protein, possibly affecting its interaction with partner proteins. Finally, we found that the mutant protein enhances cellular growth. Conclusions: We report a novel mutation in the CDC73 gene that may underlie HPT-JT syndrome. This mutation appears to affect the C-terminal moiety of the encoded protein, which is thought to interact with other protein partners. The identification of these partners may be instrumental for our understanding of the CDC73-associated phenotype. [ABSTRACT FROM AUTHOR]

Organophosphates (OPs) are routinely used as pesticides in agriculture and as insecticides within the household. Our prior work on Reelin and APOE delineated a gene–environment interactive model of autism pathogenesis, whereby genetically vulnerable individuals prenatally exposed to OPs during critical periods in neurodevelopment could undergo altered neuronal migration, resulting in an autistic syndrome. Since household use of OPs is far greater in the USA than in Italy, this model was predicted to hold validity in North America, but not in Europe. Here, we indirectly test this hypothesis by assessing linkage/association between autism and variants of the paraoxonase gene (PON1) encoding paraoxonase, the enzyme responsible for OP detoxification. Three functional single nucleotide polymorphisms, PON1 C−108T, L55M, and Q192R, were assessed in 177 Italian and 107 Caucasian-American complete trios with primary autistic probands. As predicted, Caucasian-American and not Italian families display a significant association between autism and PON1 variants less active in vitro on the OP diazinon (R192), according to case–control contrasts (Q192R: χ2=6.33, 1 df, P<0.025), transmission/disequilibrium tests (Q192R: TDT χ2=5.26, 1 df, P<0.025), family-based association tests (Q192R and L55M: FBAT Z=2.291 and 2.435 respectively, P<0.025), and haplotype-based association tests (L55/R192: HBAT Z=2.430, P<0.025). These results are consistent with our model and provide further support for the hypothesis that concurrent genetic vulnerability and environmental OP exposure may possibly contribute to autism pathogenesis in a sizable subgroup of North American individuals.Molecular Psychiatry (2005) 10, 1006–1016. doi:10.1038/sj.mp.4001714; published online 19 July 2005 [ABSTRACT FROM AUTHOR]

Autistic disorder (MIM 209850) is currently viewed as a neurodevelopmental disease. Reelin plays a pivotal role in the development of laminar structures including the cerebral cortex, hippocampus, cerebellum and of several brainstem nuclei. Neuroanatomical evidence is consistent with Reelin involvement in autistic disorder. In this study, we describe several polymorphisms identified using RNA-SSCP and DNA sequencing. Association and linkage were assessed comparing 95 Italian patients to 186 ethnically-matched controls, and using the transmission/disequilibrium test and haplotype-based haplotype relative risk in 172 complete trios from 165 families collected in Italy and in the USA. Both case-control and family-based analyses yield a significant association between autistic disorder and a polymorphic GGC repeat located immediately 5' of the reelin gene (RELN) ATG initiator codon, as well as with specific haplotypes formed by this polymorphism with two single-base substitutions located in a splice junction in exon 6 and within exon 50. Triplet repeats located in 5' untranslated regions (5'UTRs) are indicative of strong transcriptional regulation. Our findings suggest that longer triplet repeats in the 5'UTR of the RELN gene confer vulnerability to autistic disorder. [ABSTRACT FROM AUTHOR]