Linkage of congenital isolated adrenocorticotropic hormone deficiency to the corticotropin releasing hormone locus using simple sequence repeat polymorphisms

Journal Article · Fri Mar 29 04:00:00 EST 1996 · American Journal of Medical Genetics

DOI:https://doi.org/10.1002/(SICI)1096-8628(19960329)62:3<262::AID-AJMG11>3.3.CO;2-I· OSTI ID:426142

Kyllo, J H; Collins, M M; Vetter, K L ^[1]

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1. Univ. of Iowa College of Medicine, Iowa City, IA (United States); and others

Genetic screening techniques using simple sequence repeat polymorphisms were applied to investigate the molecular nature of congenital isolated adrenocorticotropic hormone (ACTH) deficiency. We hypothesize that this rare cause of hypocortisolism shared by a brother and sister with two unaffected sibs and unaffected parents is inherited as an autosomal recessive single gene mutation. Genes involved in the hypothalamic-pituitary axis controlling cortisol sufficiency were investigated for a causal role in this disorder. Southern blotting showed no detectable mutations of the gene encoding pro-opiomelanocortin (POMC), the ACTH precursor. Other candidate genes subsequently considered were those encoding neuroendocrine convertase-1, and neuroendocrine convertase-2 (NEC-1, NEC-2), and corticotropin releasing hormone (CRH). Tests for linkage were performed using polymorphic di- and tetranucleotide simple sequence repeat markers flanking the reported map locations for POMC, NEC-1, NEC-2, and CRH. The chromosomal haplotypes determined by the markers flanking the loci for POMC, NEC-1, and NEC-2 were not compatible with linkage. However, 22 individual markers defining the chromosomal haplotypes flanking CRH were compatible with linkage of the disorder to the immediate area of this gene of chromosome 8. Based on these data, we hypothesize that the ACTH deficiency in this family is due to an abnormality of CRH gene structure or expression. These results illustrate the useful application of high density genetic maps constructed with simple sequence repeat markers for inclusion/exclusion studies of candidate genes in even very small nuclear families segregating for unusual phenotypes. 25 refs., 5 figs., 2 tabs.

• OSTI ID: 426142
• Journal Information: American Journal of Medical Genetics, Journal Name: American Journal of Medical Genetics Journal Issue: 3 Vol. 62; ISSN 0148-7299; ISSN AJMGDA
• Country of Publication: United States
• Language: English

Related Subjects

55 BIOLOGY AND MEDICINE
BASIC STUDIES
ACTH
BIOLOGICAL MARKERS
CONGENITAL DISEASES
CORTICOSTEROIDS
DNA SEQUENCING
GENE MUTATIONS
GENE REGULATION
GENES
GENETIC MAPPING
HEREDITARY DISEASES
HUMAN CHROMOSOME 8
HUMAN CHROMOSOMES
HYDROCORTISONE
METABOLIC DISEASES
NUCLEOTIDES
PATIENTS
PHENOTYPE
RECESSIVE MUTATIONS
STRUCTURE-ACTIVITY RELATIONSHIPS