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C A Vogler

Publications and source records attributed to C A Vogler.

24 records · Page 2Linked to original sources
PubMed1989

Murine mucopolysaccharidosis type VII. Characterization of a mouse with beta-glucuronidase deficiency.

We have characterized a new mutant mouse that has virtually no beta-glucuronidase activity. This biochemical defect causes a murine lysosomal storage disease that has many interesting similarities to human mucopolysaccharidosis type VII (MPS VII; Sly syndrome; beta-glucuronidase deficiency). Genetic analysis showed that the mutation is inherited as an autosomal recessive that maps to the beta-glucuronidase gene complex, [Gus], on the distal end of chromosome 5. Although there is a greater than 200-fold reduction in the beta-glucuronidase mRNA concentration in mutant tissues, Southern blot analysis failed to detect any abnormalities in the structural gene, Gus-sb, or in 17 kb of 5' flanking and 4 kb of 3' flanking sequences. Surprisingly, a sensitive S1 nuclease assay indicated that the relative level of kidney gusmps mRNA responded normally to androgen induction by increasing approximately 11-fold. Analysis of this mutant mouse may offer valuable information on the pathogenesis of human MPS VII and provide a useful system in which to study bone marrow transplantation and gene transfer methods of therapy.

Alleles↗
PubMed1988

Nodular renal blastema and metanephric hamartomas in children with urinary tract malformations: a morphologic spectrum of abnormal metanephric differentiation.

In a retrospective review, we identified a variety of abnormal immature and differentiated metanephric tissues including nodular renal blastema and metanephric hamartomas in 12 children with urinary tract malformations with or without renal dysplasia. Four infants also had trisomy. Nodular renal blastema was characterized by small subcapsular clusters of primitive metanephric cells, in some cases with evidence of tubular, papillary, or trabecular differentiation. Metanephric hamartomas included papillary adenomas and tubular hamartomas. Undifferentiated renal blastema was multifocal, but more differentiated blastema usually occurred as isolated nodules. When accompanied by renal dysplasia, blastema tended to show differentiation. One child had a spectrum of lesions with both blastema and more differentiated metanephric hamartomas.

Adolescent↗
PubMed1987

Type 1 fiber size disproportion: morphometric data from 37 children with myopathic, neuropathic, or idiopathic hypotonia.

We reviewed clinical data and quantitative muscle biopsy data from infants with hypotonia and developmental delay who had relatively small type 1 muscle fibers (fiber size disproportion; FSD). Study material consisted of 49 thigh muscle specimens from 37 patients, 1 week to 11.5 years old, who had FSD diagnosed between 1971 and 1985. Beyond 2 months of age, FSD was greater than 12% in at least one biopsy from all but 2 patients. In sequential specimens obtained from 11 patients, we observed that FSD may resolve, persist unchanged, or intensify with age. In 6 patients, hypotonia regressed, and development tended to normalize during 1-4 years of observation; FSD resolved in 4 cases, but numerical predominance of type 1 fibers persisted in 3 of them. In a small group designated congenital myopathy with FSD only, the disproportion in fiber diameter persisted unchanged or intensified with time and was more severe after the age of 6 months than in the other subgroups. We classified FSD as definitely or probably myopathic (15 cases), definitely or probably neuropathic (17 cases), and benign maturation delay (5 cases). Six of 17 neuropathic cases had a history of perinatal asphyxia. In most cases, type 1 fibers were absolutely small and type 2 fibers were hypertrophied, independent of classification. FSD is a manifestation of muscle maturation delay of variable etiology. The prevalence of nervous system disorders in our series suggests that neuronal dysfunction plays an important role in pathogenesis. We were unable to define morphometric criteria that consistently distinguished congenital myopathy with FSD from definable neuropathic FSD or from benign maturation delay.

Asphyxia Neonatorum↗
PubMedDate not supplied

Donor cell replacement in mice transplanted in utero is limited by immune-independent mechanisms.

In utero transplantation (IUTx) therapy with allogeneic cells results in negligible peripheral blood (PBL) chimerism in nonablated humans with progressive diseases. IUTx has been successful only in immunocompromised fetuses. Because early treatment has great potential for halting disease progression, mechanisms preventing cell expansion must be identified and corrected. The hypothesis that factors in addition to allogenicity are responsible for low-level expansion is tested here by transplanting congenic cells into nonablated normal and mucopolycaccharidosis type VII (MPSVII) murine fetuses. MPSVII mice lack the enzyme beta-glucuronidase (GUSB-), accumulate glycosaminoglycans, and progressively develop severe storage disease. Low levels of enzyme can reverse storage. Evidence presented elsewhere showed that allogeneic donor cells overexpressing GUSB are negligible and their corrective effects are lost post-IUTx in MPSVII mice. We find that (1) congenic donor PBL cells, like allogeneic cells, are negligible in PBL of normal GUSB+ and MPSVII GUSB- hosts post-IUTx; (2) congenic, unlike allogeneic cells, are retained long term in both GUSB+ and GUSB- recipients; and (3) sufficient GUSB is produced to alleviate storage for up to 11.5 months in multiple tissues of GUSB- hosts. GUSB+ and GUSB- animals repopulate to a similar extent, indicating that donor GUSB enzyme does not initiate an immune response in the MPSVII null recipients. We conclude that the initial expansion of congenic and allogeneic cells is limited post-IUTx by non-immune-related mechanisms and the level of PBL cells is not necessarily indicative of graft failure following congenic IUTx. The mechanism limiting initial expansion may differ from that supporting long-term cell retention.

Animals↗
PubMedDate not supplied

Reversal of pathology in murine mucopolysaccharidosis type VII by somatic cell gene transfer.

An inherited deficiency of beta-glucuronidase in humans, mice and dogs causes mucopolysaccharidosis VII (Sly syndrome), a progressive degenerative disease that reduces lifespan (to an average of 5 months in mice) and results from lysosomal storage of undegraded glycosaminoglycans in the spleen, liver, kidney, cornea, brain and skeletal system. Bone marrow transplantation in mutant mice provides a source of normal enzyme ('cross-correction'), which substantially improves the clinical condition and extends the average lifespan to 18 months. Gene therapy by transfer of a beta-glucuronidase gene into mutant haematopoietic stem cells is an alternative approach, but it is not known whether the low expression of vector-transferred genes in vivo would be sufficiently effective. Here we show that retroviral vector-mediated transfer of the gene to mutant stem cells results in long-term expression of low levels of beta-glucuronidase which partially corrects the disease by reducing lysosomal storage in liver and spleen.

Animals↗