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Insertional mutation at the ld locus (again!) in a line of transgenic mice.

In the course of generating transgenic mice for studies of glial cell biology in the peripheral nervous system, we identified a line of mice in which the transgene has induced a mutation at the limb deformity (ld) locus. Mice from this line were prepared using a 3.6 kb gene construct which includes 1.1 kb of 5' flanking sequence from the rat myelin protein zero gene (Mpz) (a gene expressed specifically in myelinating Schwann cells) fused to a mutant simian virus 40 early region (tsA-1609). The line is designated Tg(Mpz, SV40E) Bril37. The male founder developed thymic hyperplasia but had no other manifestations of large T-antigen expression, and no T-antigen could be detected by immunofluorescence screening of multiple tissues from this mouse. Similarly, offspring from this founder showed no evidence of T-antigen expression. Hemizygous transgenic mice bred with B6SJLFl non-transgenic mice generated a total of 17 phenotypically normal offspring. When hemizygous transgenic mice were interbred, 18/103 offspring (the results of three separate pairings) were born with an obvious limb deformity affecting all four limbs. Both males and females were affected. DNA samples from 83 of the 103 offspring were analyzed by quantitative dot hybridization with a transgene-specific probe. All of the mice with the limb deformity were homozygous for the transgene, suggesting that the line carries an autosomal recessive insertional mutation. The skeletal malformations included oligodactyly and partial fusions of the radius-ulna and tibia-fibula, carpals, metacarpals, tarsals, and metatarsals. The axial skeleton and skull were normal. Unilateral renal aplasia (either side) was found in three of nine homozygous animals examined. Because of the striking similarity of the phenotype of our homozygous mice with that reported for recessive mutants at the ld locus (ldJ, ldOR, and ldTgHd) (1), we performed a complementation test between hemizygous TgBri137 mice and ldJ heterozygotes obtained from the Jackson Laboratory. Thirty-two mice were born to four hemizygous transgenic females mated with two ldJ heterozygous males; 16 inherited the transgene. Eight of the 16 transgenic offspring in these litters displayed the same limb deformity phenotype as that seen in the homozygous transgenic animals. Renal aplasia was observed in one of five mice examined among the transgenic X ldJ offspring. We conclude that the TgBril37 line of transgenic mice carries an insertional mutation at the ld locus (allele designated ldTgBri). It is remarkable that this same locus was the site of a previous insertional mutation caused by integration of a MMTV-myc transgene (2). It may be that the ld locus is unusually susceptible to integration by foreign DNA. However, the phenotype of non-lethal limb deformity may have been observed twice simply because it is an easy one to detect in routine screening of mouse colonies.