Disheveled hair and ear (Dhe), a spontaneous mouse Lmna mutation modeling human laminopathies.
BACKGROUND
Investigations of naturally-occurring mutations in animal models provide important insights and valuable disease models. Lamins A and C, along with lamin B, are type V intermediate filament proteins which constitute the proteinaceous boundary of the nucleus. LMNA mutations in humans cause a wide range of phenotypes, collectively termed laminopathies. To identify the mutation and investigate the phenotype of a spontaneous, semi-dominant mutation that we have named Disheveled hair and ear (Dhe), which causes a sparse coat and small external ears in heterozygotes and lethality in homozygotes by postnatal day 10.


RESULTS
Genetic mapping identified a point mutation in the Lmna gene, causing a single amino acid change, L52R, in the coiled coil rod domain of lamin A and C proteins. Cranial sutures in Dhe/+ mice failed to close. Gene expression for collagen types I and III in sutures was deficient. Skulls were small and disproportionate. Skeletons of Dhe/+ mice were hypomineralized and total body fat was deficient in males. In homozygotes, skin and oral mucosae were dysplastic and ulcerated. Nuclear morphometry of cultured cells revealed gene dose-dependent blebbing and wrinkling.


CONCLUSIONS
Dhe mice should provide a useful new model for investigations of the pathogenesis of laminopathies.
Odgren
Paul R
PR
Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
Pratt
Craig H
CH
Mackay
Carole A
CA
Mason-Savas
April
A
Curtain
Michelle
M
Shopland
Lindsay
L
Ichicki
Tsutomu
T
Sundberg
John P
JP
Donahue
Leah Rae
LR
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D004195:Disease Models, Animal; D000072261:Dishevelled Proteins; D005260:Female; D005838:Genotype; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics*; D017354:Point Mutation
D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; D034904:Lamin Type A; D010750:Phosphoproteins