Analysis Tools
mortality/aging
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• 28% of homozygotes die within the first 200 days of life
• after 250 days, ~32% of homozygotes are found dead, whereas no postnatal death is recorded for wild-type mice
• however, no abnormalities in growth, weight development, fertility, and blood or serum, parameters are observed
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renal/urinary system
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• when normalized to osmolality, the urine of homozygotes shows a decreased level of glucose
• however, the level of electrolytes, urea and creatinin remain normal
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• homozygotes show a 5-fold reduction in urine osmolality relative to wild-type mice
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albuminuria
(
J:82474
)
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• a 70 kDa protein representing albumin is found in the urine of some homozygotes indicating renal glomerular damage
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leukocyturia
(
J:82474
)
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• homozygotes show an increased number of leucocytes in urine, suggesting infection of the urogenital tract system
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• homozygotes develop a dilatation of calyces starting at 3 months of age
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• homozygotes develop a dilatation of the renal pelvis starting at 3 months of age
• at autopsy, most homozygotes (aged 3-16 months) exhibit massive hydronephrosis, which is either unilateral (with 65% on the left side) or bilateral
• uni- or bilateral hydronephrosis is caused by an obstruction of the urinary tract between renal pelvis and ureter
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• hypertrophy of the smooth muscle layer
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• even in non-hydronephrotic kidneys, the mucosa at the ureteropelvic junction shows papillary proliferations instead of an entirely smooth surface
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• at 16 months of age, homozygotes exhibit a uretero-pelvic obstruction, due to hyperproliferation of the mucosa at the ureteropelvic junction reducing the ureteric lumen to a narrow cleft
• uretero-pelvic obstruction is associated with metaplasia of the ureteric urothelium into simple columnar epithelium and hypertrophy of the smooth muscle layer
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• at 16 months of age, surface cells of the urothelium display a massive accumulation of vesicular structures, most likely of lysosomal origin
• uretero-pelvic obstruction is associated with metaplasia of the ureteric urothelium into simple columnar epithelium and hypertrophy of the smooth muscle layer
• in regions with preserved urothelium, perturbed apical expression of uroplakin suggests an impairment of membrane transport process
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• homozygotes display an increased urine volume of ~6 ml/day relative to 0.9 ml/day in wild-type male mice
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homeostasis/metabolism
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• when normalized to osmolality, the urine of homozygotes shows a decreased level of glucose
• however, the level of electrolytes, urea and creatinin remain normal
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• homozygotes show a 5-fold reduction in urine osmolality relative to wild-type mice
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albuminuria
(
J:82474
)
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• a 70 kDa protein representing albumin is found in the urine of some homozygotes indicating renal glomerular damage
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leukocyturia
(
J:82474
)
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• homozygotes show an increased number of leucocytes in urine, suggesting infection of the urogenital tract system
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hearing/vestibular/ear
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• homozygotes show eventual loss of cochlear IHCs
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• homozygotes display a gradual decrease and finally loss of cochlear OHCs, beginning at ~6 months
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• at 6 months, the stria vascularis is reduced in width
(J:82474)
• the first detectable morphological alterations of stria vascularis are first evident at ~2 months of age
(J:121998)
• at 6 months, the strial epithelium is atrophic but still identifiable, although the strial cell types are not readily distinguished
(J:121998)
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• at 2 months, endostrial capillary profiles are inconspicuous
• at 6 months, endostrial capillaries are surrounded by a thick layer of intensely stained extracellular matrix
• by 14 months, endostrial capillary profiles are absent
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• at 6 months, the three cell layers of stria vascularis are still present, but the interdigitating processes of marginal cells are completely lost
(J:82474)
• in the cytoplasm of marginal cells abnormal vacuoles are observed, while the pericapillary extracellular matrix extends between the epithelial cells, is of increased electron density, and contains deposits of globular structures
(J:82474)
• at 2 months, the basal folds of marginal cells display irregularities and are absent in some places
(J:121998)
• at 6 months, marginal cells have completely lost their basal folds
(J:121998)
• as early as 4 weeks of age and coincident with a significant reduction of hearing thresholds at frequencies above 10 kHz, homozygotes show an almost complete loss of expression of the potassium channel KCNQ1, its beta subunit KCNE1, and megalin protein in the luminal surfaces of strial marginal cells of high-frequency processing cochlear turns
(J:121998)
• cochlear turns processing frequencies below 10 kHz display partially intact
KCNQ1/KCNE1/megalin expression
(J:121998)
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• homozygotes display atrophy of the stria vascularis beginning at the age of 2 months
(J:82474)
• by 14 months, the cellular organization of stria vascularis is completely disrupted and endostrial capillary profiles are absent
(J:121998)
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• the statolith membrane is severely reduced in height
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• otoliths are absent and a layer of cells of unknown nature is detected where normally otoliths are functioning
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• no EP is detectable in a 9-month-old homozygote
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• at 6 months of age, two homozygotes display drastically reduced EPs ranging between 10 and 20 mV
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• as early as 4 weeks of age, expression of KCNQ1/KCNE1 and megalin is reduced/lost in the dark cells of the vestibular system
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• at 7 months of age, homozygotes show severely impaired brainstem auditory evoked potential (BAEP) responses relative to wild-type mice
(J:82474)
• at 2.5 months of age, homozygotes show a significant threshold loss for click stimuli, as shown by a frequency specific loss of 15-46 dB at >11.3 kHz
(J:121998)
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• at 2.5 months of age, homozygotes show a significant threshold loss of up to 29 dB at high frequencies of >8 kHz relative to wild-type mice
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• homozygotes develop complete deafness by 3-7 months of age but still show acoustic startle responses and normal brainstem auditory evoked potential (BAEP) responses at 2 months of age
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• homozygotes exhibit a progressive high-frequency hearing loss between 1 and 3 months of age
• the earliest symptoms of impaired hearing function are evident in a subset of one-month-old homozygotes, with all mutants showing decreased hearing ability at the age of 2.5 months
• gradual deterioration of hearing thresholds occurs between 1 and 6 months of age, progressing from higher towards lower frequencies
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nervous system
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• as early as 4 weeks of age, expression of KCNQ1/KCNE1 and megalin is reduced/lost in the dark cells of the vestibular system
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• homozygotes develop a progressive demyelinating neuropathy which is restricted to the peripheral nervous system
• at young ages, nerve diameter is increased due to a widening of the empty space between the nerve fibres; at 6 months or later, the amount of endoneural collagen fibrils is increased
• nerve fibres are typically thinner and surrounded by several layers of Schwann cell processes
• peripheral nerves are affected to differing degrees, with the following decreasing order: saphenus nerve > sciatic nerve > phrenic nerve > facial nerve embedded in petrous bone
• notably, the acoustic nerve does not show indications of hypertrophic neuropathy
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• homozygotes show eventual loss of cochlear IHCs
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• homozygotes display a gradual decrease and finally loss of cochlear OHCs, beginning at ~6 months
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• at 16 months, Schwann cells often contain abnormal dense inclusions and vacuoles with the outer cytoplasmic zone; these dense inclusions are similar to those seen in the urothelium
• notably, Schwann cells display an upregulation of lysosomal enzymes concomittant with a down-regulation of peripheral myelin proteins
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• with increasing age, the neurons of the spiral ganglion and nerve fibres are greatly reduced in number
(J:82474)
• by 9 months, mutant neurons amount to 85% of age-matched wild-type mice, whereas in two older homozygotes of 12 and 16 months, the number is reduced to ~20% of age-matched wild-type mice
(J:82474)
• at 6 months, homozygotes display a massive decline of spiral ganglion neurons in the cochlea, concomitant with a loss of IHCs and OHCs
(J:121998)
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• at 16 months, the diameter of phrenic nerve is increased to ~150% of wild-type mice, associated with a reduction of the total number of nerve fibres per phrenic nerve by ~20%
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demyelination
(
J:82474
)
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• homozygotes develop degenerative demyelination of the peripheral nerves
• demyelinization is associated with a massive loss of peripheral myelin proteins and an increased activity and expression of lysosomal proteins
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behavior/neurological
polydipsia
(
J:82474
)
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• homozygotes exhibit a 2/3-fold increase in water uptake relative to wild-type littermates
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• at 7 months of age, homozygotes show no or only a very weak reaction to acoustic stimuli
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growth/size/body
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• with increasing age, homozygotes display an enlarged, ball-like trunk
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cardiovascular system
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• at 2 months, endostrial capillary profiles are inconspicuous
• at 6 months, endostrial capillaries are surrounded by a thick layer of intensely stained extracellular matrix
• by 14 months, endostrial capillary profiles are absent
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