Schindler disease: The molecular lesion in the α-N-acetylgalactosaminidase gene that causes an infantile neuroaxonal dystrophy

A. M. Wang, D. Schindler, R. J. Desnick

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44 Scopus citations

Abstract

Schindler disease is a recently recognized infantile neuroaxonal dystrophy resulting from the deficient activity of the lysosomal hydrolase, α-N-acetylgalactosaminidase (α-GalNAc). The recent isolation and expression of the full-length cDNA encoding α-GalNAc facilitated the identification of the molecular lesions in the affected brothers from family D, the first cases described with this autosomal recessive disease. Southern and Northern hybridization analyses of DNA and RNA from the affected homozygotes revealed a grossly normal α-GalNAc gene structure and normal transcript sizes and amounts. Therefore, the α-GalNAc transcript from an affected homozygote was reverse-transcribed, amplified by the polymerase chain reaction (PCR), and sequenced. A single G to A transition at nucleotide 973 was detected in multiple subclones containing the PCR products. This point mutation resulted in a glutamic acid to lysine substitution in residue 325 (E325K) of the α-GalNAc polypeptide. The base substitution was confirmed by dot blot hybridization analyses of PCR-amplified genomic DNA from family members with allele-specific oligonucleotides. Furthermore, transient expression of an α-Gal-NAc construct containing the E325K mutation resulted in the expression of an immunoreactive polypeptide which had no detectable α-GalNAc activity.

Original languageEnglish
Pages (from-to)1752-1756
Number of pages5
JournalJournal of Clinical Investigation
Volume86
Issue number5
DOIs
StatePublished - 1990

Keywords

  • lysosomal hydrolase
  • neuroaxonal dystrophy
  • polymerase chain reaction
  • α-N-acetylgalactosaminidase

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