ECE2015 Guided Posters Adrenal (8 abstracts)
Autoimmune polyendocrine syndrome in India: clinical aspects, AIRE mutations, and functional analysis
Eesh Bhatia 1 , Ghazala Zaidi 1 , Aditya Sarangi 2 , Vijayalakshmi Bhatia 1 , Nisha Bharani 3 , Alok Sachan 4 , Li Zhang 5 , Liping Yu 5 , Vandana Jain 6 , Saroj Sahu 1 , Rashmi Srivastava 7 , Niharika Bharti 1 , Rakesh Aggarwal 2 & Amita Aggarwal 7
1Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India; 2Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India; 3Department of Endocrinology, Amrita Institute of Medical Sciences, Kochi, India; 4Department of Endocrinology, Sri Venkateshwara Institute of Medical Sciences, Tirupathi, India; 5Department of Immunology, Barbara Davis Center for Childhood Diabetes, Denver, India; 6Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India; 7Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
Introduction: Autoimmune polyendocrine syndrome 1 (APS1) is an uncommon, serious autosomal recessive disorder, due to AIRE gene mutations which result in impaired central tolerance. India has a complex genetic structure and also communities with high prevalence of consanguinity, which may result in varied clinical manifestations and genetic mutations.
Aims: To study clinical features, interferon-α antibodies (IFNA), AIRE mutations, and in-silico functional analysis of novel mutations in Indian patients with APS1.
Patients and methods: Twenty patients (17 families) with clinical features of APS1 were studied. Nine patients previously reported by us (Clin Genet 2009 76 441) were included in the analysis. Clinical features (including mortality on follow-up), IFNA, bidirectional sequencing of AIRE gene, and in-silico functional analysis of novel AIRE mutations were studied.
Results: Patients had three (n=9), two (n=9), or a single (n=2, family members) major manifestation of APS1, in addition to various other organ-specific autoimmune disorders. On follow-up, mortality was high (n=6, 30%), occurring at early age (5–23 years). IFNA was elevated with high titres in all patients, but was within normal range in family members with heterozygous mutations/WT sequence. Ten different mutations were detected, with C322fsX372 being most frequent (six families). Novel mutations included p.V80G (n=3, in three different families from an in-bred community in Kerala, South India), p.L11P, p.C302X, and p.X546L+59aa (c.1637G>T; terminal codon). The Finn-major mutation, R257X, was present in one patient. No specific genotype–phenotype correlation was observed. Functional analysis of two novel missense mutations (V80G and L11P) in the CARD domain revealed increased instability resulting from changes in intra-helical hydrogen binding.
Conclusions: Indian patients with APS1 syndrome had high mortality. IFNA was an inexpensive and sensitive marker for APS1. Multiple different AIRE mutations were present, including four novel mutations. Functional analysis of novel mutations revealed disruption of intra-helical hydrogen binding and increased instability.
Disclosure: This work was supported by an intra-mural research grant from Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
Volume 37
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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