Fig. 1.

Titration of the SMN protein and overt phenotypes of the Burgheron mutants. (A) The genetic make-up of the Burgheron mouse was as follows: The mutants are compound heterozygotes for the Smn1^tm1Msd knockout of SMN1 from the Sendtner laboratory and the Smn1^tm5 (aka “C”) allele from Regeneron; they also carry a single copy of the human SMN2^89Ahmb transgene. (B) SMN protein expression in the Burgheron mutants, measured by ELISA, is lower than in SMN^C mutants but higher than in Δ7 mutants, in both the spinal cord and brain tissue, making the Burgheron mouse an intermediate SMA model. There was a very significant effect of the genotype on SMN levels; Burgheron mice were significantly different and displayed SMN levels intermediary between C/C and Δ7 mutants (Dunnett’s multiple comparison tests, 0.15: P = 0.15). (C) Survival of Burgheron mice is longer than for Δ7 mice (median survival, 18 d) but shorter than for C/C mutants (median survival, >400 d; Mantel–Cox log-rank test, P < 0.001); there is no difference between the survival of male and female Burgheron mice (P = 0.14; median survival, 102 and 98.5 d, respectively). (D) Growth curves of control (WT, n = 77, black), C/C (n = 100, green), Bugheron (n = 33, red), and Δ7 (n = 41, orange) mice. Body weight (BW) at given ages were compared by Student t test, and major significance differences are indicated in the text. (E) Necrosis affects the tail of the Burgheron mutants as early as PND 10 (mutants, n = 20, black squares; littermate controls, n = 38, open circles).