ExperimentName: Plaa G23V/G23V homozygous mice

NonHumanModel: mus musculus

GeneAlteration: Crispr/Cas9 gene editing was used to successfully mutate the mouse Plaa gene with a patient derived variant, G23V (mouse c. 68G>T) (Figure 3 and Figure S4). From the first round of injections, the obtained 33 mice, in which 3 had the c.68G>T variation alone/ solely. Confirmation of the change was performed by Sanger sequencing in the founder mice.

ModelPhenotype: HP:0004325, HP:0002808, HP:0001337, HP:0012448

HumanPhenotype: HP:0012448

ModelEvidence: Plaa G23V homozygous mice are viable past birth, but cannot survive past 6 months without assistance of feeding, etc (Figure 3B). The mutant show microcephaly (reduced brain volume, Figure 3C). MRI performed on the G23V homozygous mice compared with control wildtype littermates show significantly reduced corpus callosum and cerebellum volumes, indicating reduced white matter (Figure 3E). The cerebellum is noted to have disrupted foliation (figure S5C). The authors note early onset neurodysfunction, including tremor and muscle weakness , showing severe hindlimb clasping, reduced grip strength and altered gait detectable from P14 (Figure 3 and Figure S5).

They authors even went on to cross the Plaa G23V heterozygous mice with Plaa homozygous null mice to create Plaa G23V/- mice that have a more severe phenotype that the homozygous Plaa G23V homozygous, but less severe that the Plaa homozygous null (plaa-/-).

EvidenceShown: Figure 3, Figure S3-6,

ModelVariant: NM_001031689.2(PLAA):c.68G>T (p.Gly23Val)

ClinVar ID: 427941

Score:

Reason: This mouse model represents a patient derived mutation that was knocked directly into the mouse Plaa locus, through use of Crispr/Cas9 gene editing. The mice were shown to have reduced Plaa protein expression (reduced by 70%), and the development of phenotypes consistent with phenotypes observed in individuals. I have therefore, increased the score based on the evidence provided.

Score: 3

ExperimentName: Plaa G23V/G23V homozygous mice

NonHumanModel: mus musculus

GeneAlteration: Crispr/Cas9 gene editing was used to successfully mutate the mouse Plaa gene with a patient derived variant, G23V (mouse c. 68G>T) (Figure 3 and Figure S4). From the first round of injections, the obtained 33 mice, in which 3 had the c.68G>T variation alone/ solely. Confirmation of the change was performed by Sanger sequencing in the founder mice.

ModelPhenotype: HP:0004325, HP:0002808, HP:0001337, HP:0012448

HumanPhenotype: HP:0012448

ModelEvidence: Plaa G23V homozygous mice are viable past birth, but cannot survive past 6 months without assistance of feeding, etc (Figure 3B). The mutant show microcephaly (reduced brain volume, Figure 3C). MRI performed on the G23V homozygous mice compared with control wildtype littermates show significantly reduced corpus callosum and cerebellum volumes, indicating reduced white matter (Figure 3E). The cerebellum is noted to have disrupted foliation (figure S5C). The authors note early onset neurodysfunction, including tremor and muscle weakness , showing severe hindlimb clasping, reduced grip strength and altered gait detectable from P14 (Figure 3 and Figure S5).

They authors even went on to cross the Plaa G23V heterozygous mice with Plaa homozygous null mice to create Plaa G23V/- mice that have a more severe phenotype that the homozygous Plaa G23V homozygous, but less severe that the Plaa homozygous null (plaa-/-).

EvidenceShown: Figure 3, Figure S3-6,

ModelVariant: NM_001031689.2(PLAA):c.68G>T (p.Gly23Val)

ClinVar ID: 427941

Score:

Reason: This mouse model represents a patient derived mutation that was knocked directly into the mouse Plaa locus, through use of Crispr/Cas9 gene editing. The mice were shown to have reduced Plaa protein expression (reduced by 70%), and the development of phenotypes consistent with phenotypes observed in individuals. I have therefore, increased the score based on the evidence provided.

Score: 3