Journal article
A knockin mouse model of the Bardet-Biedl syndrome 1 M390R mutation has cilia defects, ventriculomegaly, retinopathy, and obesity
Proceedings of the National Academy of Sciences of the United States of America, Vol.104(49), pp.19422-19427
12/04/2007
DOI: 10.1073/pnas.0708571104
PMCID: PMC2148305
PMID: 18032602
Abstract
Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder that results in retinal degeneration, obesity, cognitive impairment, polydactyly, renal abnormalities, and hypogenitalism. Of the 12 known BBS genes, BBS1 is the most commonly mutated, and a single missense mutation (M390R) accounts for approximately 80% of BBS1 cases. To gain insight into the function of BBS1, we generated a Bbs1 super(M390R/M390R) knockin mouse model. Mice homozygous for the M390R mutation recapitulated aspects of the human phenotype, including retinal degeneration, male infertility, and obesity. The obese mutant mice were hyperphagic and hyperleptinemic and exhibited reduced locomotor activity but no elevation in mean arterial blood pressure. Morphological evaluation of Bbs1 mutant brain neuroanatomy revealed ventriculomegaly of the lateral and third ventricles, thinning of the cerebral cortex, and reduced volume of the corpus striatum and hippocampus. Similar abnormalities were also observed in the brains of Bbs2 super(-/-), Bbs4 super(-/-), and Bbs6 super(-/-) mice, establishing these neuroanatomical defects as a previously undescribed BBS mouse model phenotype. Ultrastructural examination of the ependymal cell cilia that line the enlarged third ventricle of the Bbs1 mutant brains showed that, whereas the 9 + 2 arrangement of axonemal microtubules was intact, elongated cilia and cilia with abnormally swollen distal ends were present. Together with data from transmission electron microscopy analysis of photoreceptor cell connecting cilia, the Bbs1 M390R mutation does not affect axonemal structure, but it may play a role in the regulation of cilia assembly and/or function.
Details
- Title: Subtitle
- A knockin mouse model of the Bardet-Biedl syndrome 1 M390R mutation has cilia defects, ventriculomegaly, retinopathy, and obesity
- Creators
- Roger E. DavisRuth E. SwiderskiKamal RahmouniDarryl Y. NishimuraRobert F. MullinsKhristofor AgassandianAlisdair R. PhilpCharles C. SearbyMichael P. AndrewsStewart ThompsonChristopher J. BerryDaniel R. ThedensBaoli Yang - University of IowaRobert M. WeissMartin D. CassellEdwin M. StoneVal C. Sheffield
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences of the United States of America, Vol.104(49), pp.19422-19427
- DOI
- 10.1073/pnas.0708571104
- PMID
- 18032602
- PMCID
- PMC2148305
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Language
- English
- Date published
- 12/04/2007
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Radiology; Electrical and Computer Engineering; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; BioVentures Center; Obstetrics and Gynecology; Neuroscience and Pharmacology; Internal Medicine; Ophthalmology and Visual Sciences
- Record Identifier
- 9983557417302771
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