Positional cloning of "Lisch-Like", a candidate modifier of susceptibility to type 2 diabetes in mice

• Published in: PLoS genetics 2008-07, Vol.4 (7), p.e1000137-e1000137
• Main Authors: Dokmanovic-Chouinard, Marija, Chung, Wendy K, Chevre, Jean-Claude, Watson, Elizabeth, Yonan, Jason, Wiegand, Beebe, Bromberg, Yana, Wakae, Nao, Wright, Chris V, Overton, John, Ghosh, Sujoy, Sathe, Ganesh M, Ammala, Carina E, Brown, Kathleen K, Ito, Rokuro, LeDuc, Charles, Solomon, Keely, Fischer, Stuart G, Leibel, Rudolph L
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Base Sequence; Blood Glucose - genetics; Cell division; Chromosomes, Mammalian; Cloning, Molecular; Crosses, Genetic; Danio rerio; Diabetes; Diabetes and Endocrinology/Type 2 Diabetes; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Type 2 - genetics; Gene expression; Genetic Predisposition to Disease; Genetics; Genetics and Genomics/Complex Traits; Genetics and Genomics/Gene Discovery; Glucose Tolerance Test - methods; Haplotypes; Homozygote; Hyperglycemia; Insulin - blood; Insulin resistance; Male; Mice; Mice, Congenic; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Obese; Molecular Sequence Data; Mortality; Mutation; Obesity; Physiology/Endocrinology; Protein Isoforms - chemistry; Protein Isoforms - genetics; Proteins; Quantitative Trait Loci; Receptors, Cell Surface - genetics
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1000137

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.