Positional cloning of "Lisch-Like", a candidate modifier of susceptibility to type 2 diabetes in mice.
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.
Dokmanovic-Chouinard
Marija
M
Naomi Berrie Diabetes Center, Columbia University, New York, New York, USA.
Chung
Wendy K
WK
Chevre
Jean-Claude
JC
Watson
Elizabeth
E
Yonan
Jason
J
Wiegand
Beebe
B
Bromberg
Yana
Y
Wakae
Nao
N
Wright
Chris V
CV
Overton
John
J
Ghosh
Sujoy
S
Sathe
Ganesh M
GM
Ammala
Carina E
CE
Brown
Kathleen K
KK
Ito
Rokuro
R
LeDuc
Charles
C
Solomon
Keely
K
Fischer
Stuart G
SG
Leibel
Rudolph L
RL
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001786:Blood Glucose / Q000235:genetics; D033481:Chromosomes, Mammalian; D003001:Cloning, Molecular; D003433:Crosses, Genetic; D003921:Diabetes Mellitus, Experimental / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005951:Glucose Tolerance Test / Q000379:methods; D006239:Haplotypes; D006720:Homozygote; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008820:Mice, Obese; D008969:Molecular Sequence Data; D009154:Mutation; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics; D040641:Quantitative Trait Loci; D011956:Receptors, Cell Surface / Q000235:genetics*
D001786:Blood Glucose; D007328:Insulin; D020033:Protein Isoforms; D011956:Receptors, Cell Surface; C531361:lisch-like protein, mouse