Transglutaminase 1-deficient recessive lamellar ichthyosis associated with a LINE-1 insertion in Jack Russell terrier dogs.
BACKGROUND
Congenital, nonepidermolytic cornification disorders phenotypically resembling human autosomal recessive ichthyosis have been described in purebred dog breeds, including Jack Russell terrier (JRT) dogs. One cause of gene mutation important to humans and dogs is transposon insertions.


OBJECTIVE
To describe an autosomal recessive, severe nonepidermolytic ichthyosis resembling lamellar ichthyosis (LI) in JRT dogs due to insertion of a long interspersed nucleotide element (LINE-1) in the transglutaminase 1 (TGM1) gene.


METHODS
Dogs were evaluated clinically, and skin samples were examined by light and electron microscopy. Phenotypic information and genotyping with a canine microsatellite marker suggested TGM1 to be a candidate gene. Genomic DNA samples and cDNA generated from epidermal RNA were examined. Consequences of the mutation were evaluated by Western blotting, quantitative reverse transcription-polymerase chain reaction (RT-PCR) and enzyme activity from cultured keratinocytes.


RESULTS
Affected dogs had generalized severe hyperkeratosis. Histological examination defined laminated to compact hyperkeratosis without epidermolysis; ultrastructurally, cornified envelopes were thin. Affected dogs were homozygous for a 1980-bp insertion within intron 9 of TGM1. The sequence of the insertion was that of a canine LINE-1 element. Quantitative RT-PCR indicated a significant decrease in TGM1 mRNA in affected dogs compared with wild-type. TGM1 protein was markedly decreased on immunoblotting, and membrane-associated enzyme activity was diminished in affected dogs.


CONCLUSIONS
Based on morphological and molecular features, this disease is homologous with TGM1-deficient LI in humans, clinically models LI better than the genetically modified mouse and represents its first spontaneous animal model. This is the first reported form of LI due to transposon insertion.
Credille
K M
KM
Department of Veterinary Pathobiology, Texas A&M University, College Station, TX, USA. credillekm@lilly.com
Minor
J S
JS
Barnhart
K F
KF
Lee
E
E
Cox
M L
ML
Tucker
K A
KA
Diegel
K L
KL
Venta
P J
PJ
Hohl
D
D
Huber
M
M
Dunstan
R W
RW
D000818:Animals; D001706:Biopsy / Q000662:veterinary; D004251:DNA Transposable Elements / Q000235:genetics; D004283:Dog Diseases / Q000235:genetics* / Q000473:pathology; D004285:Dogs; D005260:Female; D005819:Genetic Markers; D017490:Ichthyosis, Lamellar / Q000235:genetics / Q000473:pathology / Q000662:veterinary*; D007150:Immunohistochemistry; D007438:Introns / Q000235:genetics; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D008297:Male; D016254:Mutagenesis, Insertional / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000662:veterinary; D012867:Skin / Q000473:pathology; D013045:Species Specificity; D011503:Transglutaminases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
D004251:DNA Transposable Elements; D005819:Genetic Markers; D012333:RNA, Messenger; D011503:Transglutaminases; C105804:transglutaminase 1