Mouse Genome Informatics
hm
    Iduatm1Efn/Iduatm1Efn
involves: C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       
mortality/aging
• homozygotes live for about 1 year

immune system
• homozygotes exhibit otitis media at 2 months, 6 months and one year of age; not observed in wild-type or heterozygous mice at any age
• at 6 months, a subset of microglia in the cortex (sometimes perineuronal) consists of cells that appear to be phagocytic, with enormous vacuoles that are empty or contain flocculent material and resemble lysosomes engorged with glycosaminoglycan (GAG)
• in the cortex, a subset of activated perineural microglia are shown to contain large storage vacuoles, react with MOMA-2 (monoclonal antibody against macrophages) and Griffonia simplicifolia isolectin IB4, and stain intensely for lysosomal proteins as well as for GM3 ganglioside
• MOMA-2-positive cells appear at 6 months, but although their number increases with age, they remain scanty
• activation of resident microglia, an influx and activation of blood monocytes, or both is indicated by a profusion of cells carrying the macrophage CD68/macrosialin antigen in the cortex at 1 month, as well as increases in CD68/macrosialin mRNA and other transcripts associated with macrophage functions

nervous system
• by 12 months of age, cochlear hair cells are totally lost
• however, no hair cell loss is noted at 2 or 6 months
• at 6 months, a subset of microglia in the cortex (sometimes perineuronal) consists of cells that appear to be phagocytic, with enormous vacuoles that are empty or contain flocculent material and resemble lysosomes engorged with glycosaminoglycan (GAG)
• in the cortex, a subset of activated perineural microglia are shown to contain large storage vacuoles, react with MOMA-2 (monoclonal antibody against macrophages) and Griffonia simplicifolia isolectin IB4, and stain intensely for lysosomal proteins as well as for GM3 ganglioside
• MOMA-2-positive cells appear at 6 months, but although their number increases with age, they remain scanty
• activation of resident microglia, an influx and activation of blood monocytes, or both is indicated by a profusion of cells carrying the macrophage CD68/macrosialin antigen in the cortex at 1 month, as well as increases in CD68/macrosialin mRNA and other transcripts associated with macrophage functions
• at 6 months, homozygotes exhibit large, nearly empty inclusions in perineural microglia in the cortex
• by 12 months of age, neurofilaments are missing in all homozygotes; some ganglion cells contain lysosomal vacuoles and a few remain myelinated

craniofacial
• at 6 months, affected homozygotes display craniofacial (esp. skull base) abnormalities, with notable sex differences
• in addition, affected homozygotes show a significant increase in midocular distance relative to unaffected control mice
• at 6 months, affected male homozygotes display a significant decrease in the width of the skull base at mandibular condyles relative to unaffected control mice
• at 6 months, affected female homozygotes display a significant decrease in the height of the foramen magnum relative to unaffected control mice
• at 6 months, affected male homozygotes display a significant increase in the width of the zygoma at the maxilla relative to unaffected control mice
• at 6 months, affected male homozygotes display a significant increase in the spread of mandibular condyles relative to unaffected control mice
• at 6 months, affected male homozygotes display insertion of the incisors to the foramen magnum
• at this age, affected female homozygotes display insertion of the lower incisors to the vertex of skull
• at 6 months, both male and female affected homozygotes display a significant increase in the width of the skull base between the external auditory canals relative to unaffected control mice

skeleton
• at 6 months, affected male homozygotes display a significant decrease in the width of the skull base at mandibular condyles relative to unaffected control mice
• at 6 months, affected female homozygotes display a significant decrease in the height of the foramen magnum relative to unaffected control mice
• at 6 months, affected male homozygotes display a significant increase in the width of the zygoma at the maxilla relative to unaffected control mice
• at 6 months, affected male homozygotes display a significant increase in the spread of mandibular condyles relative to unaffected control mice
• at 6 months, homozygotes display damage and loss of fibrocytes in the lateral cochlear wall
• at 6 months, affected female homozygotes display a significant decrease in the width of the cervical canal relative to unaffected control mice

hearing/vestibular/ear
• at 6 months, both male and female affected homozygotes display a significant increase in the width of the skull base between the external auditory canals relative to unaffected control mice
• at 2 months, homozygotes display cells containing lysosomal granules and vacuoles in various regions of the inner ear, except for the stria vascularis and hair cells
• by 12 months of age, cochlear hair cells are totally lost
• however, no hair cell loss is noted at 2 or 6 months
• by 12 months of age, the organ of Corti is totally missing in all homozygotes
• in contrast, the morphology of stria vascularis remains normal at 12 months
• at 6 months, homozygotes display damage and loss of fibrocytes in the lateral cochlear wall
• at 2 months, homozygotes display elevated ABR thresholds (55.8 dB) relative to wild-type and heterozygous mice (30 dB and 31.8 dB, respectively) in response to clicks and tone bursts over a 1-32 kHz range
• by 6 months, homozygotes show increased ABR thresholds at frequencies of 12 kHz and 16 kHz, and are totally deaf above and below these frequencies relative to wild-type and heterozygous mice
• at 1 year of age, homozygotes are completely deaf, with no detectable ABR responses at any test frequencies
• hearing loss progresses from mild to moderate loss at 2 months to profound at 6 months and total deafness by 12 months of age
• homozygotes exhibit otitis media at 2 months, 6 months and one year of age; not observed in wild-type or heterozygous mice at any age

cardiovascular system
• aortic elastic fibers are discontinuous, exhibiting splitting and interruptions
• homozygotes display vacuolation and distention of smooth muscle fibers in the medial layer of the aortic wall
• the mitral valve is grossly enlarged and misshapen
• in the mitral valve, endothelial cells are only moderately vacuolated, whereas interstitial cells are very heavily vacuolated
• restoration of enzyme activity in the heart of one mouse, by transplantation of retrovirally modified bone marrow, resulted in loss of storage vacuoles in endothelial cells from the mitral valve, but not in valvular interstitial cells
• the tricuspid valve is grossly enlarged and misshapen
• in the endocardium, endothelial cells appear swollen, subjacent myocardial fibers are discontinuous due to aggregates of vacuolated cells between them, and perinuclear vacuoles are found in many myocytes
• in the myocardium, the interstitial space between myocardial cells is distended by aggregates of vacuolated interstitial cells and deposits of collagen
• restoration of enzyme activity in the heart of one mouse, by transplantation of retrovirally modified bone marrow, resulted in loss of storage vacuoles in myocytes
• within myocytes, homozygotes contain numerous empty vacuoles, which are of variable size and are lined up along the mitochondria
• however, sarcomeres, Z-disks. and intercalated disks appear structurally normal
• at 6 months, homozygotes display enlarged hearts, as verified by echocardiography of left ventricular chamber dimensions
• heart enlargement is more prominent at 10 months than at 6 months of age
• however, no increased myocyte mass or dilated chambers are observed
• homozygotes display a concentric ventricular enlargement from thicker walls due primarily to the infiltration of non-myocyte cells laden with storage material
• at 10 months, the septal ventricular walls are significantly thicker than normal
• at 6 and 10 months, the heart weight relative to either body weight or to tibia length is significantly increased relative to age-matched wild-type mice
• at 10 months, the left ventricular outflow tracts are significantly enlarged
• the aortic valve is grossly enlarged and misshapen, with a significantly thickened valve leaflet
• at 10 months, both the septal and posterior walls of left ventricles are significantly thicker, without enlargement of the inner chamber diameters
• as early as 6 months of age, homozygotes display ventricular dysfunction by echocardiography
• by 10 months, both Vcf (an index of contractile function) and ejection fraction are markedly reduced, with a significant reduction in +dP/dT (an index of contractility) noted at both 6 and 10 months
• at both ages, homozygotes show significantly longer ejection times (65 2 ms vs 56 2 ms in wild-type mice), a reduction in maximum blood flow velocity (Vmax) and in peak pressure gradient (PPG) across the aortic valve
• despite impaired ventricular function and valvular regurgitation, free-roaming homozygotes display surprisingly normal heart rates and blood pressures relative to wild-type mice at 10 months of age
• restoration of enzyme activity in the heart of one mouse, by transplantation of retrovirally modified bone marrow, resulted in normalization of left ventricular function
• at 6 and 10 months, homozygotes show a significant reduction in -dP/dT (an index of relaxation)
• Doppler echocardiography indicates mitral valve regurgitation with abnormally long back-flow profiles following valve closure
• Doppler echocardiography indicates aortic valve regurgitation during diastole along with a dilated left ventricular outflow tract
• despite similar heart rates, homozygotes show a significant reduction in heart rate variability (CV%) relative to wild-type mice at all times
• although PR and QT intervals are similar and within the normal range, all homozygotes display altered wave amplitudes and widths (duration)
• however, no differences in the rate of arrhythmias are observed between wild-type and mutant mice
• the P wave widths are prolonged and sometimes exhibit multiple peaks
• the QRS-Tri waves sometimes exhibit multiple peaks
• the S wave amplitudes are reduced while the Tri wave amplitudes are enlarged
• the S wave amplitude (normalized to the R wave) is diminished by 1/3 in both the light and dark cycles
• the QRS-Tri wave widths are prolonged
• within a light cycle, homozygotes display a modest, but statistically significant 6-13 mm Hg increase in systolic blood pressure relative to wild-type mice
• however, systolic and diastolic blood pressures are both increased during the active (dark cycle) period in both mutant and wild-type mice

homeostasis/metabolism
• homozygotes display significantly lower body temperatures than wild-type mice at all times
• homozygotes are devoid of alpha-L-iduronidase activity and, as a consequence, accumulate soluble glycosaminoglycan in heart muscle and aorta

muscle
• homozygotes display vacuolation and distention of smooth muscle fibers in the medial layer of the aortic wall
• within myocytes, homozygotes contain numerous empty vacuoles, which are of variable size and are lined up along the mitochondria
• however, sarcomeres, Z-disks. and intercalated disks appear structurally normal
• as early as 6 months of age, homozygotes display ventricular dysfunction by echocardiography
• by 10 months, both Vcf (an index of contractile function) and ejection fraction are markedly reduced, with a significant reduction in +dP/dT (an index of contractility) noted at both 6 and 10 months
• at both ages, homozygotes show significantly longer ejection times (65 2 ms vs 56 2 ms in wild-type mice), a reduction in maximum blood flow velocity (Vmax) and in peak pressure gradient (PPG) across the aortic valve
• despite impaired ventricular function and valvular regurgitation, free-roaming homozygotes display surprisingly normal heart rates and blood pressures relative to wild-type mice at 10 months of age
• restoration of enzyme activity in the heart of one mouse, by transplantation of retrovirally modified bone marrow, resulted in normalization of left ventricular function
• at 6 and 10 months, homozygotes show a significant reduction in -dP/dT (an index of relaxation)
• homozygotes display increased collagen deposition in heart muscle

behavior/neurological
• homozygotes fail to maintain a well-defined circadian rhythm with respect to activity, heart rate, and body temperature
• homozygotes exhibit nearly twice the activity of wild-type mice during the light (sleep) cycle, while activity patterns during the dark cycle are also perturbed
• adult homozygotes display impaired long-term memory of inhibitory avoidance, a type of single-trial aversively motivated conditioning
• however, no alterations in short-term inhibitory avoidance retention or novel object recognition memory are observed
• in addition, no changes in footshock reactivity (flinch or jump thresholds) are observed, indicating normal nociception
• adult homozygotes exhibit a reduced number of rearings during exploration of an open field, indicating reduced exploratory behavior
• however, no alterations in locomotion (number of crossings) or anxiety (latency to start locomotion and number of fecal pellets) are observed

cellular
• at 2 months, homozygotes display cells containing lysosomal granules and vacuoles in the region of type I, II, III and IV fibrocytes of the spiral ligament (with type IV fibrocytes most severely affected and type III least affected), as well as in the spiral prominence, spiral limbus, mesothelial cells lining the basilar membrane, both epithelial and mesothelial cells of Reisnner's membrane, endothelial cells of vessels, and some spiral ganglion cells
• no cells containing lysosomal granules and vacuoles are noted in the inner ears of newborn mice
• no cells with lysosomal storage granules are noted in the stria vascularis or cochlear hair cells at any age
• the number of lysosomal storage vacuoles found in the inner ear increases with aging, as shown at 6 and 12 months of age

hematopoietic system
• at 6 months, a subset of microglia in the cortex (sometimes perineuronal) consists of cells that appear to be phagocytic, with enormous vacuoles that are empty or contain flocculent material and resemble lysosomes engorged with glycosaminoglycan (GAG)
• in the cortex, a subset of activated perineural microglia are shown to contain large storage vacuoles, react with MOMA-2 (monoclonal antibody against macrophages) and Griffonia simplicifolia isolectin IB4, and stain intensely for lysosomal proteins as well as for GM3 ganglioside
• MOMA-2-positive cells appear at 6 months, but although their number increases with age, they remain scanty
• activation of resident microglia, an influx and activation of blood monocytes, or both is indicated by a profusion of cells carrying the macrophage CD68/macrosialin antigen in the cortex at 1 month, as well as increases in CD68/macrosialin mRNA and other transcripts associated with macrophage functions

growth/size/body
• at 6 months, affected male homozygotes display insertion of the incisors to the foramen magnum
• at this age, affected female homozygotes display insertion of the lower incisors to the vertex of skull
• at 6 months, both male and female affected homozygotes display a significant increase in the width of the skull base between the external auditory canals relative to unaffected control mice

Mouse Models of Human Disease
OMIM IDRef(s)
Hurler Syndrome 607014 J:81974 , J:101932 , J:117424
Hurler-Scheie Syndrome 607015 J:81974
Otitis Media, Susceptibility to 166760 J:123676
Scheie Syndrome 607016 J:81974