PUBLICATION
Positional cloning of "Lisch-Like", a candidate modifier of susceptibility to type 2 diabetes in mice
- Authors
- Dokmanovic-Chouinard, M., Chung, W.K., Chevre, J.C., Watson, E., Yonan, J., Wiegand, B., Bromberg, Y., Wakae, N., Wright, C.V., Overton, J., Ghosh, S., Sathe, G.M., Ammala, C.E., Brown, K.K., Ito, R., LeDuc, C., Solomon, K., Fischer, S.G., and Leibel, R.L.
- ID
- ZDB-PUB-080801-21
- Date
- 2008
- Source
- PLoS Genetics 4(7): e1000137 (Journal)
- Registered Authors
- Solomon, Keely, Wright, Christopher V.E.
- Keywords
- Diabetes mellitus, Zebrafish, Insulin, Embryos, Morpholino, Complementary DNA, Gene pool, Blood sugar
- MeSH Terms
-
- Amino Acid Sequence
- Animals
- Base Sequence
- Blood Glucose/genetics
- Chromosomes, Mammalian
- Cloning, Molecular
- Crosses, Genetic
- Diabetes Mellitus, Experimental/genetics*
- Diabetes Mellitus, Type 2/genetics*
- Genetic Predisposition to Disease*
- Glucose Tolerance Test/methods
- Haplotypes
- Homozygote
- Insulin/blood
- Male
- Mice
- Mice, Congenic
- Mice, Inbred C57BL
- Mice, Inbred DBA
- Mice, Obese
- Molecular Sequence Data
- Mutation
- Protein Isoforms/chemistry
- Protein Isoforms/genetics
- Quantitative Trait Loci
- Receptors, Cell Surface/genetics*
- PubMed
- 18654634 Full text @ PLoS Genet.
Citation
Dokmanovic-Chouinard, M., Chung, W.K., Chevre, J.C., Watson, E., Yonan, J., Wiegand, B., Bromberg, Y., Wakae, N., Wright, C.V., Overton, J., Ghosh, S., Sathe, G.M., Ammala, C.E., Brown, K.K., Ito, R., LeDuc, C., Solomon, K., Fischer, S.G., and Leibel, R.L. (2008) Positional cloning of "Lisch-Like", a candidate modifier of susceptibility to type 2 diabetes in mice. PLoS Genetics. 4(7):e1000137.
Abstract
In 404 Lep(ob/ob) F2 progeny of a C57BL/6J (B6) x DBA/2J (DBA) intercross, we mapped a DBA-related quantitative trait locus (QTL) to distal Chr1 at 169.6 Mb, centered about D1Mit110, for diabetes-related phenotypes that included blood glucose, HbA1c, and pancreatic islet histology. The interval was refined to 1.8 Mb in a series of B6.DBA congenic/subcongenic lines also segregating for Lep(ob). The phenotypes of B6.DBA congenic mice include reduced beta-cell replication rates accompanied by reduced beta-cell mass, reduced insulin/glucose ratio in blood, reduced glucose tolerance, and persistent mild hypoinsulinemic hyperglycemia. Nucleotide sequence and expression analysis of 14 genes in this interval identified a predicted gene that we have designated "Lisch-like" (Ll) as the most likely candidate. The gene spans 62.7 kb on Chr1qH2.3, encoding a 10-exon, 646-amino acid polypeptide, homologous to Lsr on Chr7qB1 and to Ildr1 on Chr16qB3. The largest isoform of Ll is predicted to be a transmembrane molecule with an immunoglobulin-like extracellular domain and a serine/threonine-rich intracellular domain that contains a 14-3-3 binding domain. Morpholino knockdown of the zebrafish paralog of Ll resulted in a generalized delay in endodermal development in the gut region and dispersion of insulin-positive cells. Mice segregating for an ENU-induced null allele of Ll have phenotypes comparable to the B.D congenic lines. The human ortholog, C1orf32, is in the middle of a 30-Mb region of Chr1q23-25 that has been repeatedly associated with type 2 diabetes.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping