Positional Cloning of “Lisch-like”, a Candidate Modifier of Susceptibility to Type 2 Diabetes in Mice

Abstract

In 404 Lepob/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 Lepob. The phenotypes of B6.DBA congenic mice include reduced β-cell replication rates accompanied by reduced β-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.

Insights into obesity and diabetes at the intersection of mouse and human genetics

“…The Lisch-like ( Ll) gene was positionally cloned in an ob/ob F2 intercross between C57BL/6J (B6) and the diabetes prone DBA/2J (DBA) strains (71) as a gene underlying a T2D locus on chromosome 1 and was shown to be involved in regulating β-cell mass and plasma glucose levels.…”

“…Mice with reduced LI expression have impaired β-cell development and glucose metabolism (71). Reduced expression of the homologous gene in zebrafish disrupts islet development (71).…”

“…Mice with reduced LI expression have impaired β-cell development and glucose metabolism (71). Reduced expression of the homologous gene in zebrafish disrupts islet development (71). Interestingly the human ortholog of LI has been associated with T2D in several populations (72-77).…”

High-Fat, Carbohydrate-Free Diet Markedly Aggravates Obesity but Prevents β-Cell Loss and Diabetes in the Obese, Diabetes-Susceptible <i>db/db</i> Strain

“…Rather, diabetogenic alleles contributed by the C57BL/KsJ background are responsible for the β-cell loss of the db/db strain. Recently, the major diabetogenic allele of the C57BL/KsJ background on chromosome 1 has been identified as a variant of the Lisch-like gene [20]. At present, it cannot be excluded that the NZO strain carries a different diabetogenic allele of this gene.…”

Structure and Function of the Lipolysis Stimulated Lipoprotein Receptor

“…Finally, a homolog to LSR was identified by positional cloning with similar alternativelysliced mRNA products, that could potentially relate to the susceptibility of mice to type 2 diabetes (Dokmanovic-Chouinard et al, 2008). Indeed, LSR does not demonstrate any distinct homology to other known receptors, which is why little is known about the relationship between its structure and function.…”