Source:http://linkedlifedata.com/resource/pubmed/id/20963592
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
9-10
|
| pubmed:dateCreated |
2010-11-5
|
| pubmed:databankReference | |
| pubmed:abstractText |
Using genome-wide mutagenesis with N-ethyl-N-nitrosourea (ENU), a mouse mutant with cryptorchidism was identified. Genome mapping and exon sequencing identified a novel missense mutation (D294G) in Relaxin/insulin-like family peptide receptor 2 (Rxfp2). The mutation impaired testicular descent and resulted in decreased testis weight in Rxfp2 ( DG/DG ) mice compared to Rxfp2 (+/DG ) and Rxfp2 (+/+) mice. Testicular histology of the Rxfp2 ( DG/DG ) mice revealed spermatogenic defects ranging from germ cell loss to tubules with Sertoli-cell-only features. Genetic complementation analysis using a loss-of-function allele (Rxfp2 (-)) confirmed causality of the D294G mutation. Specifically, mice with one of each mutant allele (Rxfp2 ( DG/-)) exhibited decreased testis weight and failure of the testes to descend compared to their Rxfp2 (+/-) littermates. Total and cell-surface expression of mouse RXFP2 protein and intracellular cAMP accumulation were measured. Total expression of the D294G protein was minimally reduced compared to wild-type, but cell-surface expression was markedly decreased. When analyzed for cAMP accumulation, the EC50 was similar for cells transfected with wild-type and mutant RXFP2 receptor. However, the maximum cAMP response that the mutant receptor reached was greatly reduced compared to the wild-type receptor. In silico modeling of leucine rich repeats (LRRs) 7-9 indicated that aspartic acid 294 is located within the ?-pleated sheet of LRR8. We thus postulate that mutation of D294 results in protein misfolding and aberrant trafficking. The ENU-induced D294G mutation underscores the role of the INSL3/RXFP2-mediated pathway in testicular descent and expands the repertoire of mutations known to affect receptor trafficking and function.
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| pubmed:grant | |
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical | |
| pubmed:status |
MEDLINE
|
| pubmed:month |
Oct
|
| pubmed:issn |
1432-1777
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| pubmed:author |
pubmed-author:AgoulnikAlexander IAI,
pubmed-author:BarrettTimT,
pubmed-author:BathgateRoss A DRA,
pubmed-author:EmgeDonnaD,
pubmed-author:FinlaysonCourtneyC,
pubmed-author:FisherLisaL,
pubmed-author:HarrisRebecca MRM,
pubmed-author:HurleyLisaL,
pubmed-author:JamesonJ LarryJL,
pubmed-author:WeissJeffreyJ
|
| pubmed:issnType |
Electronic
|
| pubmed:volume |
21
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
442-9
|
| pubmed:dateRevised |
2011-9-22
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| pubmed:meshHeading |
pubmed-meshheading:20963592-Animals,
pubmed-meshheading:20963592-Chromosome Mapping,
pubmed-meshheading:20963592-Cryptorchidism,
pubmed-meshheading:20963592-DNA Mutational Analysis,
pubmed-meshheading:20963592-Disease Models, Animal,
pubmed-meshheading:20963592-Ethylnitrosourea,
pubmed-meshheading:20963592-Gene Knockout Techniques,
pubmed-meshheading:20963592-Genetic Complementation Test,
pubmed-meshheading:20963592-Male,
pubmed-meshheading:20963592-Mice,
pubmed-meshheading:20963592-Mice, Inbred C57BL,
pubmed-meshheading:20963592-Models, Molecular,
pubmed-meshheading:20963592-Molecular Sequence Data,
pubmed-meshheading:20963592-Mutagenesis,
pubmed-meshheading:20963592-Mutation, Missense,
pubmed-meshheading:20963592-Polymerase Chain Reaction,
pubmed-meshheading:20963592-Protein Conformation,
pubmed-meshheading:20963592-Protein Folding,
pubmed-meshheading:20963592-Receptors, G-Protein-Coupled,
pubmed-meshheading:20963592-Signal Transduction,
pubmed-meshheading:20963592-Testis
|
| pubmed:year |
2010
|
| pubmed:articleTitle |
A missense mutation in LRR8 of RXFP2 is associated with cryptorchidism.
|
| pubmed:affiliation |
Department of Medicine, Feinberg School of Medicine, Northwestern University, Arthur J. Rubloff Building, 420 E. Superior St., Suite 12-109, Chicago, IL 60611, USA.
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
|