Neurologic, Gastric, and Opthalmologic Pathologies in a Murine Model of Mucolipidosis Type IV

• Published in: American journal of human genetics Vol. 81; no. 5; pp. 1070 - 1083
• Main Authors: Venugopal, Bhuvarahamurthy, Browning, Marsha F., Curcio-Morelli, Cyntia, Varro, Andrea, Michaud, Norman, Nanthakumar, Nanda, Walkley, Steven U., Pickel, James, Slaugenhaupt, Susan A.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01-11-2007; University of Chicago Press; Cell Press; American Society of Human Genetics
• Subjects: Animals; Biological and medical sciences; Body Weight; Carbohydrates (enzymatic deficiencies). Glycogenosis; Digestive system; Disease Models, Animal; Errors of metabolism; Eye Diseases - complications; Eye Diseases - pathology; Fundamental and applied biological sciences. Psychology; Gastric Mucosa - pathology; Gastric Mucosa - ultrastructure; Gastrins - blood; Gene Targeting; General aspects. Genetic counseling; Genes; Genetics of eukaryotes. Biological and molecular evolution; Hindlimb - pathology; Inclusion Bodies - ultrastructure; Longevity; Medical genetics; Medical sciences; Metabolic diseases; Mice; Mice, Knockout; Molecular and cellular biology; Mucolipidoses - complications; Mucolipidoses - pathology; Nervous System Diseases - complications; Nervous System Diseases - pathology; Neurology; Ophthalmology; Paralysis - pathology; Pathology; Pyramidal Cells - ultrastructure; Retinal Degeneration - pathology; Rodents; Stomach Diseases - complications; Stomach Diseases - pathology; Survival Analysis; Transient Receptor Potential Channels; TRPM Cation Channels - deficiency; Human; Stomach; Animal model; Nervous system diseases; Rodentia; Metabolic diseases; Enzymopathy; Genetic disease; Eye disease; Vertebrata; Anatomic pathology; Mammalia; Mucolipidosis IV; Mouse; Genetics; Carbohydrate
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/521954

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.