Cardiac manifestations in the mouse model of mucopolysaccharidosis I

Abstract

Mucopolysaccharidosis I (MPS I, α-l-iduronidase deficiency disease) is a heritable lysosomal storage disorder involving multiple organs, including the heart. Malfunction of the heart is also a major manifestation in the mouse model of MPS I, progressing in severity from 6 to 10 months (of a 1 year life span). In comparisons of MPS I with wild-type mice, the heart was found enlarged, with thickened septal and posterior walls, primarily because of infiltration of the muscle by storage-laden cells. Heart valves were enlarged and misshapen, and contained large numbers of highly vacuolated interstitial cells. The thickened aortic wall contained vacuolated smooth muscle cells and interrupted elastic fibers. Hemodynamic measurements and echocardiography revealed reduced left ventricular function as well as mitral and aortic regurgitation. But despite these abnormalities, free-roaming MPS I mice implanted with radio telemetry devices showed surprisingly normal heart rate and blood pressure, though their electrocardiograms were abnormal. An incidental finding of the telemetry studies was a disturbed circadian rhythm in the MPS I mice. Restoration of enzyme activity in the heart of one mouse, by transplantation of retrovirally modified bone marrow, resulted in normalization of left ventricular function as well as loss of storage vacuoles in myocytes and endothelial cells, though not in valvular interstitial cells. This study demonstrates the usefulness of the mouse model for in-depth studies of the cardiovascular component of MPS I.

Introduction

Mucopolysaccharidosis I (MPS I) is an autosomal recessive disorder caused by mutation of the IDUA gene; the resulting deficiency of the lysosomal enzyme α-l-iduronidase causes accumulation of its substrates, dermatan sulfate and heparan sulfate [1]. The disorder is clinically heterogeneous, the clinical spectrum ranging from the very severe Hurler syndrome to the attenuated Scheie syndrome, with a diverse group of intermediate severity known as Hurler–Scheie (OMIM # 67014, 67016, and 67015, respectively). Heart disease, corneal clouding, organomegaly, skeletal malformations, and joint stiffness are present in varying degrees in all forms of MPS I, while significant mental retardation is present in the severe form only. Life span is generally limited to childhood in the severe form and early adulthood in the intermediate form, but can be normal in the most attenuated form. Molecular heterogeneity is the probable cause of the clinical variability, with a combination of mutant alleles determining the clinical phenotype. Eighty-nine mutations of the IDUA gene are listed in the Human Gene Mutation Data Base [2], only a few of which are common.

Cardiovascular disease is a prominent feature of Hurler syndrome and had been noted in early descriptions of the disease (reviewed in [3]). Myocardial thickening, occlusion of coronary arteries, and valvular disease are common in all forms of MPS I [4], [5], [6], [7]. Systemic or pulmonary hypertension occurs in some MPS I patients [4], [8], [9], [10], [11]. Congestive heart failure is a frequent cause of death in the severe form of MPS I [9], while valve replacement is often necessary in the attenuated forms [1].

Animal models of MPS I are being used to study pathogenesis and develop therapy. These include the naturally occurring MPS I dog [12] and cat [13] models, and two very similar knockout mouse models [14], [15], [16]. We have used the mouse model developed in our laboratory [16] to study cardiac malfunction; a preliminary account of this work has been presented in abstract form [17].