New leptin receptor mutations in mice: Lepr(db-rtnd), Lepr(db-dmpg) and Lepr(db-rlpy).
Three new spontaneous recessive mouse mutations in the leptin receptor gene (Lepr), Lepr(db-rtnd), Lepr(db-dmpg) and Lepr(db-rlpy), originated in the CBA/J (CBA), B10.D2-H8(b)(57N)/Sn (B10) and NU/J strains, respectively. Lepr(db-rtnd) and Lepr(db-dmpg) were maintained on C57BL/6J (B6), resulting in congenic lines of B6.CBA-Lepr(db-rtnd) and B6.B10-Lepr(db-dmpg). Lepr(db-rtnd) was also maintained on CBA post F1 generation of a cross between the B6 and the CBA, generating the congenic line CBA.B6CBA-Lepr(db-rtnd). Lepr(db-rlpy) was maintained as a coisogenic strain. The aims of this study were to determine the molecular bases for these new Lepr mutations and to characterize the new mutant stocks, with respect to obesity and diabetes. Mutations were analyzed by Southern blot analysis, reverse transcriptase-polymerase chain reaction and sequencing. Body weights and plasma glucose and insulin levels were measured, and the histology of the pancreas was carried out. Lepr(db-rtnd) contained one G deletion in exon 4 of Lepr, introducing a frameshift and premature termination. Lepr(db-dmpg) had a deletion in the extracellular domain of LEPR: Lepr(db-rlpy) exhibited a large DNA deletion, leading to a complete lack of LEPR: All three mutations led to morbid obesity and diabetes. It is noteworthy that Lepr(db-rtnd) caused milder hyperglycemia accompanied by higher plasma and pancreatic insulin contents on B6 compared to that on CBA backgrounds. In summary, we discovered three new mutations of Lepr, providing new mouse models for obesity and diabetes. Furthermore, our mutant stocks will be useful in elucidating the effects of the genetic background on the Lepr mutations and in testing the specificity of antibodies to LEPR.
Kim
Jung Han
JH
Department of Nutrition, The University of Tennessee, Knoxville, TN 37996, USA. jhkim@utk.edu
Taylor
Paul N
PN
Young
Dawn
D
Karst
Son Yong
SY
Nishina
Patsy M
PM
Naggert
Jürgen K
JK
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D003433:Crosses, Genetic; D017931:DNA Primers; D003920:Diabetes Mellitus / Q000235:genetics; D005260:Female; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation; D009765:Obesity / Q000235:genetics; D010179:Pancreas / Q000473:pathology; D011956:Receptors, Cell Surface / Q000235:genetics*; D054411:Receptors, Leptin; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D017931:DNA Primers; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; C515447:leptin receptor, mouse