Polymorphisms at +49A/G and CT60 sites in the 3′ UTR of the CTLA‐4 gene and APECED‐related AIRE gene mutations analysis in sporadic idiopathic hypoparathyroidism

Goswami, Ravinder; Gupta, Nidhi; Ray, Debarti; Rani, Rajni; Tomar, Neeraj; Sarin, Ritu; Vupputuri, Madhava Rao

doi:10.1111/j.1744-313x.2005.00545.x

Cited by 18 publications

(21 citation statements)

References 35 publications

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“…1,37,38 Another study did not find APS I-related AIRE gene mutations in patients with sporadic idiopathic hypoparathyroidism. 39 Moreover, Figure 2 A schematic figure of the large deletion in the two APS I patients N1 (Norwegian patient) and D2 (Danish patient). The deletion spans from exon 2 until exon 8, but does not go beyond the end of intron 9 (confirmed for patient N1).…”

Section: Discussionmentioning

confidence: 99%

AIRE variations in Addison's disease and autoimmune polyendocrine syndromes (APS): partial gene deletions contribute to APS I

et al. 2008

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Autoimmune Addison's disease (AAD) is often associated with other components in autoimmune polyendocrine syndromes (APS). Whereas APS I is caused by mutations in the AIRE gene, the susceptibility genes for AAD and APS II are unclear. In the present study, we investigated whether polymorphisms or copy number variations in the AIRE gene were associated with AAD and APS II. First, nine SNPs in the AIRE gene were analyzed in 311 patients with AAD and APS II and 521 healthy controls, identifying no associated risk. Second, in a subgroup of 25 of these patients, AIRE sequencing revealed three novel polymorphisms. Finally, the AIRE copy number was determined by duplex quantitative PCR in 14 patients with APS I, 161 patients with AAD and APS II and in 39 healthy subjects. In two Scandinavian APS I patients previously reported to be homozygous for common AIRE mutations, we identified large deletions of the AIRE gene covering at least exon 2 to exon 8. We conclude that polymorphisms in the AIRE gene are not associated with AAD and APS II. We further suggest that DNA analysis of the parents of patients found to be homozygous for mutations in AIRE, always should be performed.

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Section: Discussionmentioning

confidence: 99%

AIRE variations in Addison's disease and autoimmune polyendocrine syndromes (APS): partial gene deletions contribute to APS I

et al. 2008

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“…The latter was considered benign because the same mutation was also present in her asymptomatic mother and brother. Besides, there was no increased prevalence of autoimmunity-related single nucleotide polymorphisms (SNPs) in the CTLA-4 and PTPN22 genes in our earlier studies in patients with IH (20,21).…”

Section: Introductionmentioning

confidence: 99%

“…The study included 101 patients with IH attending the endocrine and metabolic clinics of All India Institute of Medical Sciences, Delhi, during 1998-2008 (14,(18)(19)(20)(21). The criteria used to diagnose IH included the presence of hypocalcemia, hyperphosphatemia, and an inappropriately normal or subnormal level of serum-intact PTH (iPTH), normal renal function, and serum magnesium (2).…”

Section: Patientsmentioning

confidence: 99%

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Presence and significance of a R110W mutation in the DNA-binding domain of GCM2 gene in patients with isolated hypoparathyroidism and their family members

Tomar¹,

Bora²,

Singh³

et al. 2010

European Journal of Endocrinology

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Objective: Glial cells missing 2 (GCM2) gene encodes a parathyroid-specific transcription factor. We assessed GCM2 gene sequence in patients with isolated hypoparathyroidism (IH). Design: Case-control study. Methods: Complete DNA sequencing of the GCM2 gene including its exons, promoter, and 5 0 and 3 0UTRs was performed in 24/101 patients with IH. PCR-restriction fragment length polymorphism was used to detect a novel R110W mutation in all 101 IH patients and 655 healthy controls. Significance of the mutation was assessed by electrophoretic mobility shift assay (EMSA) and nuclear localization on transfection.Results: A heterozygous R110W mutation was present in DNA-binding domain in 11/101 patients (10.9%) and absent in 655 controls (P!10 K7 ). Four of 13 nonaffected first-degree relatives for five of these index cases had R110W mutation. Four heterozygous single nucleotide polymorphisms were found in the 5 0 region. One of the 11 patients with R110W also had T370M change in compound heterozygous form. Mutant R110W and T370M GCM2 proteins showed decreased binding with GCM recognition elements on EMSA indicating loss of function. Both wild-type and R110W mutant GCM2 proteins showed nuclear localization. Conclusions: The present study indicates a significant association of R110W variant with IH. Absence of effect of heterozygous R110W mutation on DNA binding and presence of the same mutation in asymptomatic family members indicate that additional genetic (akin to T370M change) or nongenetic factors might contribute to the expression of diseases in IH. Alternatively, it is possible that association of R110W with IH could be due to linkage disequilibrium with the unidentified relevant genes in IH.

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“…Without the familial context, such patients would probably not have been diagnosed as APS1. Notably, no AIRE gene mutation was found in 73 patients with isolated hypoparathyroidism, but only 4 common mutations were studied [24]. Several cases of poorly symptomatic or atypical forms of APS1 have already been described [25,26], supporting the proposition that the criteria for diagnosis should be reevaluated.…”

Section: Discussionmentioning

confidence: 98%

Autoimmune Polyendocrine Syndrome Type 1 in North-Western France: <i>AIRE</i> Gene Mutation Specificities and Severe Forms Needing Immunosuppressive Therapies

et al. 2010

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Background: Autoimmune polyendocrine syndrome type 1 (APS1) has been poorly evaluated in France. We focused on the north-western part of the country to describe clinical phenotypes, especially severe forms of the disease, and AIRE gene mutations. Methods: Clinical and immunological data were collected, and pathological mutations were identified by DNA sequencing. Results: Nineteen patients were identified with APS1. Clinical manifestations varied greatly, showing 1–10 components. Mucocutaneous candidiasis, adrenal failure, hypoparathyroidism, alopecia and other severe infections were the most frequent components. Four patients had severe forms, needing immunosuppressive therapy: 2 for hepatitis; 1 for severe malabsorption, and 1 for a T cell large granular lymphocytic leukemia. These therapies were very effective but caused general discomfort. One patient died of septicemia. Four different AIRE gene mutations were identified, and a 13-bp deletion in exon 8 (c.967–979del13) was the most prevalent. There was at least one allele correlating with this mutation and alopecia occurrence (p = 0.003). No novel mutation was detected. Conclusion: APS1 appears to be rare in north-western France. We identified 4 cases with a severe form needing immunosuppressive therapy. The AIRE gene mutations are more like those found in north-western Europe than those found in Finland.

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Polymorphisms at +49A/G and CT60 sites in the 3′ UTR of the CTLA‐4 gene and APECED‐related AIRE gene mutations analysis in sporadic idiopathic hypoparathyroidism

Cited by 18 publications

References 35 publications

AIRE variations in Addison's disease and autoimmune polyendocrine syndromes (APS): partial gene deletions contribute to APS I

AIRE variations in Addison's disease and autoimmune polyendocrine syndromes (APS): partial gene deletions contribute to APS I

Presence and significance of a R110W mutation in the DNA-binding domain of GCM2 gene in patients with isolated hypoparathyroidism and their family members

Autoimmune Polyendocrine Syndrome Type 1 in North-Western France: <i>AIRE</i> Gene Mutation Specificities and Severe Forms Needing Immunosuppressive Therapies

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