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A Critical Evaluation of Liver Pathology in Humans with Danon Disease and Experimental Correlates in a Rat Model of LAMP-2 Deficiency.

Authors: Wang, Lu  Wang, Jingbo  Cai, Weile  Shi, Yongquan  Zhou, Xinmin  Guo, Guanya  Guo, Changcun  Huang, Xiaofeng  Han, Zheyi  Zhang, Shuai  Ma, Shuoyi  Zhou, Xia  Fan, Daiming  Gershwin, M Eric  Han, Ying 
Citation: Wang L, etal., Clin Rev Allergy Immunol. 2017 Aug;53(1):105-116. doi: 10.1007/s12016-017-8598-3.
Pubmed: (View Article at PubMed) PMID:28124283
DOI: Full-text: DOI:10.1007/s12016-017-8598-3

Danon disease is a genetic deficiency in lysosome-associated membrane protein 2 (LAMP-2), a highly glycosylated constituent of the lysosomal membrane and characterized by a cardiomyopathy, skeletal muscle myopathy, and cognitive impairment. Patients, however, often manifest hepatic abnormalities, but liver function has not been well evaluated and the syndrome is relatively uncommon. Hence, we have taken advantage of a rat that has been deleted of LAMP-2 to study the relative role of LAMP-2 on liver function. Interestingly, rats deficient in LAMP-2 develop a striking increase in serum alkaline phosphatase (ALP) and a decrease in bile flow compared with wild-type littermates. Importantly and by ultrastructural analysis, deficient rats manifest dilated canaliculi that lack microvilli with evidence of bile-containing bodies. Moreover, following bile duct ligation, LAMP-2-deficient rats develop rapid and severe evidence of advanced cholestasis, with an increase in serum bilirubin, as early as 6 h later. In wild-type control rats, multidrug resistance-associated protein 2 (Mrp2) normally concentrates at the bile canalicular membranes to secrete conjugated bilirubin into bile. However, in LAMP-2y/- rats, Mrp2 was detected in hepatocytes compared with other canalicular proteins including P-glycoproteins, dipeptidyl peptidase IV (CD26), and aminopeptidase (CD13). Our data further suggest that LAMP-2 interacts with the membrane cytoskeletal proteins radixin and F-actin in determining the localization of integral membrane proteins.

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CRRD Object Information
CRRD ID: 13703118
Created: 2018-08-02
Species: All species
Last Modified: 2018-08-02
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.