Clinical Endocrinology

Novel polymorphisms and lack of mutations in the ACD gene in patients with ACTH resistance syndromes

Authors

  • Catherine E. Keegan,

    1. Department of Pediatrics, Division of Genetics, University of Michigan, Ann Arbor MI, USA,
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  • Janna E. Hutz,

    1. Department of Pediatrics, Division of Genetics, University of Michigan, Ann Arbor MI, USA,
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  • Andrea S. Krause,

    1. Department of Pediatrics, Division of Genetics, University of Michigan, Ann Arbor MI, USA,
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  • Katrin Koehler,

    1. Children's Hospital, Technical University Dresden, Dresden, Germany,
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  • Louise A. Metherell,

    1. Department of Endocrinology, William Harvey Research Institute, Barts & the London School of Medicine and Dentistry, Queen Mary University of London, West Smithfield, London, UK,
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  • Sosipatros Boikos,

    1. Section on Endocrinology and Genetics, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, USA,
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  • Sotirios Stergiopoulos,

    1. Section on Endocrinology and Genetics, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, USA,
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  • Adrian J. L. Clark,

    1. Department of Endocrinology, William Harvey Research Institute, Barts & the London School of Medicine and Dentistry, Queen Mary University of London, West Smithfield, London, UK,
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  • Constantine A. Stratakis,

    1. Section on Endocrinology and Genetics, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, USA,
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  • Angela Huebner,

    1. Children's Hospital, Technical University Dresden, Dresden, Germany,
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  • Gary D. Hammer

    1. Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes and
    2. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor MI, USA
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Catherine E. Keegan, Department of Pediatrics, Division of Genetics, University of Michigan Medical School, 3520 MSRB I, Box 0652, 1150 W. Medical Center Dr., Ann Arbor, MI 48109–0652, USA. Tel.: +1 (734) 647 8237; Fax: + 1 (734) 763 9512; E-mail: keeganc@med.umich.edu

Summary

Objective  ACTH resistance is a feature of several human syndromes with known genetic causes, including familial glucocorticoid deficiency (types 1 and 2) and triple A syndrome. However, many patients with ACTH resistance lack an identifiable genetic aetiology. The human homolog of the Acd gene, mutated in a mouse model of adrenal insufficiency, was sequenced in 25 patients with a clinical diagnosis of familial glucocorticoid deficiency or triple A syndrome.

Design  A 3·4 kilobase genomic fragment containing the entire ACD gene was analysed for mutations in all 25 patients.

Setting  Samples were obtained by three investigators from different institutions.

Patients  The primary cohort consisted of 25 unrelated patients, primarily of European or Middle Eastern descent, with a clinical diagnosis of either familial glucocorticoid deficiency (FGD) or triple A syndrome. Patients lacked mutations in other genes known to cause ACTH resistance, including AAAS for patients diagnosed with triple A syndrome and MC2R and MRAP for patients diagnosed with familial glucocorticoid deficiency. Thirty-five additional patients with adrenal disease phenotypes were added to form an expanded cohort of 60 patients.

Measurements  Identification of DNA sequence changes in the ACD gene in the primary cohort and analysis of putative ACD haplotypes in the expanded cohort.

Results  No disease-causing mutations were found, but several novel single nucleotide polymorphisms (SNPs) and two putative haplotypes were identified. The overall frequency of SNPs in ACD is low compared to other gene families.

Conclusions  No mutations were identified in ACD in this collection of patients with ACTH resistance phenotypes. However, the newly identified SNPs in ACD should be more closely examined for possible links to disease.

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