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Functional characterization of the molecular defects causing nephrogenic diabetes insipidus in eight families.
J Clin Endocrinol Metab. 2000 Apr; 85(4):1703-10.JC

Abstract

X-Linked nephrogenic diabetes insipidus (NDI) is a rare inherited disorder characterized by the excretion of abnormal large volumes of diluted urine mainly caused by mutations in the V2 vasopressin receptor (AVPR2) gene. By screening NDI patients for mutations within the AVPR2 gene we have identified three novel (I46K, F105V, I130F) and four recurrent (D85N, R106C, R113W, Q225X) mutations. In addition, a recurrent missense mutation (A147T) within the aquaporin-2 gene was identified in a female patient with autosomal recessive NDI associated with sensorineural deafness. Selected clinical data of the NDI patients were compared with the results from the in vitro studies. Functional analysis of I46K and I130F revealed reduced maximum agonist-induced cAMP responses as a result of an improper cell surface targeting. In contrast, the F105V mutation is delivered to the cell surface and displayed an unchanged maximum cAMP response, but impaired ligand binding abilities of F105V were reflected in a shifted concentration-response curve toward higher vasopressin concentrations. As the extracellularly located F105 is highly conserved among the vasopressin/oxytocin receptor family, functional analysis of this residue implicates an important role in high affinity agonist binding.

Authors+Show Affiliations

Institut für Pharmakologie, Freie Universität Berlin, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10770218

Citation

Pasel, K, et al. "Functional Characterization of the Molecular Defects Causing Nephrogenic Diabetes Insipidus in Eight Families." The Journal of Clinical Endocrinology and Metabolism, vol. 85, no. 4, 2000, pp. 1703-10.
Pasel K, Schulz A, Timmermann K, et al. Functional characterization of the molecular defects causing nephrogenic diabetes insipidus in eight families. J Clin Endocrinol Metab. 2000;85(4):1703-10.
Pasel, K., Schulz, A., Timmermann, K., Linnemann, K., Hoeltzenbein, M., Jääskeläinen, J., Grüters, A., Filler, G., & Schöneberg, T. (2000). Functional characterization of the molecular defects causing nephrogenic diabetes insipidus in eight families. The Journal of Clinical Endocrinology and Metabolism, 85(4), 1703-10.
Pasel K, et al. Functional Characterization of the Molecular Defects Causing Nephrogenic Diabetes Insipidus in Eight Families. J Clin Endocrinol Metab. 2000;85(4):1703-10. PubMed PMID: 10770218.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Functional characterization of the molecular defects causing nephrogenic diabetes insipidus in eight families. AU - Pasel,K, AU - Schulz,A, AU - Timmermann,K, AU - Linnemann,K, AU - Hoeltzenbein,M, AU - Jääskeläinen,J, AU - Grüters,A, AU - Filler,G, AU - Schöneberg,T, PY - 2000/4/19/pubmed PY - 2000/4/19/medline PY - 2000/4/19/entrez SP - 1703 EP - 10 JF - The Journal of clinical endocrinology and metabolism JO - J Clin Endocrinol Metab VL - 85 IS - 4 N2 - X-Linked nephrogenic diabetes insipidus (NDI) is a rare inherited disorder characterized by the excretion of abnormal large volumes of diluted urine mainly caused by mutations in the V2 vasopressin receptor (AVPR2) gene. By screening NDI patients for mutations within the AVPR2 gene we have identified three novel (I46K, F105V, I130F) and four recurrent (D85N, R106C, R113W, Q225X) mutations. In addition, a recurrent missense mutation (A147T) within the aquaporin-2 gene was identified in a female patient with autosomal recessive NDI associated with sensorineural deafness. Selected clinical data of the NDI patients were compared with the results from the in vitro studies. Functional analysis of I46K and I130F revealed reduced maximum agonist-induced cAMP responses as a result of an improper cell surface targeting. In contrast, the F105V mutation is delivered to the cell surface and displayed an unchanged maximum cAMP response, but impaired ligand binding abilities of F105V were reflected in a shifted concentration-response curve toward higher vasopressin concentrations. As the extracellularly located F105 is highly conserved among the vasopressin/oxytocin receptor family, functional analysis of this residue implicates an important role in high affinity agonist binding. SN - 0021-972X UR - https://www.unboundmedicine.com/medline/citation/10770218/Functional_characterization_of_the_molecular_defects_causing_nephrogenic_diabetes_insipidus_in_eight_families_ L2 - https://academic.oup.com/jcem/article-lookup/doi/10.1210/jcem.85.4.6507 DB - PRIME DP - Unbound Medicine ER -