TY - JOUR
T1 - Neurologic, gastric, and opthalmologic pathologies in a murine model of mucolipidosis type IV
AU - Venugopal, Bhuvarahamurthy
AU - Browning, Marsha F.
AU - Curcio-Morelli, Cyntia
AU - Varro, Andrea
AU - Michaud, Norman
AU - Nanthakumar, Nanda
AU - Walkley, Steven U.
AU - Pickel, James
AU - Slaugenhaupt, Susan A.
N1 - Funding Information:
This work was supported by National Institute of Neurological Disorders and Stroke grant NS39995 (to S.A.S.), National Institute of Diabetes and Digestive and Kidney Diseases grants DK12437 and DK70260 (to N.N.), Child Health and Development grant HD045561 (to S.U.W.), Harvard Medical School NIH Training Grant T32-GM077481-25 (to B.V.), and NIH Individual Ruth L. Kirschstein National Research Service Award (NRSA) 1F32NS052072-01A1 (to M.F.B.).
Funding Information:
We thank Harvard Partners Center for Genetics and Genomics (Gene Modification Lab) for engineering the targeting construct, Gloria Stephney for the EM work done in the brain, Matthew Micsenyi for the LAMP2-staining experiments in neurons, and Mary McKee for the EM work in the stomach. Mary McKee is at the Massachusetts General Hospital EM core, which is supported by Inflammatory Bowel Disease Center grant DK43351, Boston Area Diabetes and Endocrinology Research Center grant DK57521, and Harvard Clinical Nutrition Research Center grant DK40561.
PY - 2007
Y1 - 2007
N2 - Mucolipidosis type IV (MLIV) is an autosomal recessive lysosomal storage disorder caused by mutations in the MCOLN1 gene, which encodes the 65-kDa protein mucolipin-1. The most common clinical features of patients with MLIV include severe mental retardation, delayed motor milestones, ophthalmologic abnormalities, constitutive achlorhydria, and elevated plasma gastrin levels. Here, we describe the first murine model for MLIV, which accurately replicates the phenotype of patients with MLIV. The Mcoln1-/- mice present with numerous dense inclusion bodies in all cell types in brain and particularly in neurons, elevated plasma gastrin, vacuolization in parietal cells, and retinal degeneration. Neurobehavioral assessments, including analysis of gait and clasping, confirm the presence of a neurological defect. Gait deficits progress to complete hind-limb paralysis and death at age ∼8 mo. The Mcoln1 -/- mice are born in Mendelian ratios, and both male and female Mcoln1-/- mice are fertile and can breed to produce progeny. The creation of the first murine model for human MLIV provides an excellent system for elucidating disease pathogenesis. In addition, this model provides an invaluable resource for testing treatment strategies and potential therapies aimed at preventing or ameliorating the abnormal lysosomal storage in this devastating neurological disorder.
AB - Mucolipidosis type IV (MLIV) is an autosomal recessive lysosomal storage disorder caused by mutations in the MCOLN1 gene, which encodes the 65-kDa protein mucolipin-1. The most common clinical features of patients with MLIV include severe mental retardation, delayed motor milestones, ophthalmologic abnormalities, constitutive achlorhydria, and elevated plasma gastrin levels. Here, we describe the first murine model for MLIV, which accurately replicates the phenotype of patients with MLIV. The Mcoln1-/- mice present with numerous dense inclusion bodies in all cell types in brain and particularly in neurons, elevated plasma gastrin, vacuolization in parietal cells, and retinal degeneration. Neurobehavioral assessments, including analysis of gait and clasping, confirm the presence of a neurological defect. Gait deficits progress to complete hind-limb paralysis and death at age ∼8 mo. The Mcoln1 -/- mice are born in Mendelian ratios, and both male and female Mcoln1-/- mice are fertile and can breed to produce progeny. The creation of the first murine model for human MLIV provides an excellent system for elucidating disease pathogenesis. In addition, this model provides an invaluable resource for testing treatment strategies and potential therapies aimed at preventing or ameliorating the abnormal lysosomal storage in this devastating neurological disorder.
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U2 - 10.1086/521954
DO - 10.1086/521954
M3 - Article
C2 - 17924347
AN - SCOPUS:35348829780
SN - 0002-9297
VL - 81
SP - 1070
EP - 1083
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -