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, 95 (3), 1207-12

Constitutive Achlorhydria in Mucolipidosis Type IV

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Constitutive Achlorhydria in Mucolipidosis Type IV

R Schiffmann et al. Proc Natl Acad Sci U S A.

Abstract

Mucolipidosis type IV is an autosomal recessive lysosomal storage disease of unknown etiology that causes severe neurological and ophthalmological abnormalities. In an attempt to obtain insight into the nature of the metabolic abnormality in this disorder, we prospectively evaluated 15 consecutive patients, aged 2 to 23 years, over a period of 22 months. The finding of iron deficiency in some of the patients led us to the discovery that all patients but one had markedly elevated blood gastrin levels. None had vitamin B12 deficiency. Gastroscopy in three patients showed normal gross appearance of the mucosa in two patients, 4 and 7 years old, and mucosal atrophy in a 22-year-old. Parietal cells were present in normal numbers and contained large cytoplasmic inclusions that were confirmed immunohistochemically to be lysosomal in nature. Other gastric epithelial cells appeared normal. Parietal cells contained very few tubulovesicular membranes, suggesting cellular activation, whereas apical canaliculi appeared relatively nonactivated. Both subunits of the parietal cell H+/K+-ATPase were present, and both partially colocalized with f-actin at the apical membrane. We conclude that patients with mucolipidosis type IV are constitutively achlorhydric and have partially activated parietal cells. We hypothesize that the defective protein in this disease is closely associated with the final stages of parietal cell activation and is critical for a specific type of cellular vacuolar trafficking between the cytoplasm and the apical membrane domain.

Figures

Figure 1
Figure 1
Gastroscopic images of patients with ML-IV showing a normal mucosal surface in 4- (A) and 7-year-old (B) patients, and atrophic changes in a 22-year-old patient (C).
Figure 2
Figure 2
Biopsy of the gastric mucosa of a patient with ML-IV stained with hematoxylin and eosin. Vacuolated parietal cells are evident, whereas the mucus-secreting cells at the mucosal surface appear normal. (Magnification: ×40.)
Figure 3
Figure 3
(A) Electron micrograph of a parietal cell from stomach of a patient with Z-E showing secretory canaliculi (C) and tubulovesicles (TV); Lu, lumen. (Magnification: ×6,500.) (B) Electron micrograph of a parietal cell from the stomach of a patient with ML-IV. The parietal cell lysosomes (Ly) are large and contain structurally heterogeneous material including vesicles (V) and masses of lamellar structures (L). M, mitochondria. (Magnification: ×6,500.) (C) A similar electron micrograph showing an abnormally distended canaliculus that is identified by the cell surface microvilli. (Magnification: ×6,500.)
Figure 4
Figure 4
Lysosome distribution in parietal cells from a patient with ML-IV and a patient with Z-E. (A and C) Phase microscopy view. (B and D) The same sections as in A and C, respectively stained with fluorescein phallacidin (green) and LAMP2 antibodies (red). (Magnification: ×1,000.)
Figure 5
Figure 5
H+/K+-ATPase beta (B) and alpha (D and F) subunits distribution in parietal cells from a patient with ML-IV (AD) and patient with Z-E (E and F). Phase microscopy view (A, C, and E) and the corresponding parietal cells stained with fluorescein phallacidin in green, and anti-H+/K+-ATPase beta and alpha subunits in red (B, D, and F). (Magnification: ×1,000.)
Figure 6
Figure 6
Schematic representation of a hypothesis regarding the cellular lesion in ML-IV. Lack of hydrochloric acid secretion by parietal cells that are constantly stimulated by gastrin is accompanied by diversion of the tubulovesicular membranes (TV) into lysosomes. On the right, we show the effect of the lesion on other cell types in ML-IV. Recycling endosomes involved in a deficient plasma membrane-specific function are diverted into lysosomes. 1, H+/K+-ATPase; 2, ion channels; 3, cytoskeletal elements; 4, kinases involved in plasma membrane activation; 5, kinases and phosphatases involved in the deactivation process; 6, SNAREs; 7, G-proteins; and 8, annexins.

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