Journal article
Molecular basis of an adult form of β-hexosaminidase B deficiency with motor neuron disease
Biochemical and biophysical research communications, Vol.181(1), pp.108-115
1991
Handle:
https://hdl.handle.net/2376/103893
PMID: 1720305
Abstract
A patient (KL) with progressive motor neuron disease associated with partial Hex A (αβ) and no Hex B (ββ) activity, synthesized β-chains which only associated with α-chains. To identify the molecular basis of this inability of β-chains to self associate, RNA from cultured fibroblasts was reverse transcribed, the cDNA encoding the β-chain amplified by polymerase chain reaction, subcloned, and sequenced to reveal two types of single missense mutation. The first mutation, (Type I)
619A ➡ G, was paternally inherited and converted a
207lle ➡ Val in a highly conserved region believed to be associated with catalytic activity and activator protein binding. Biochemical evidence for impaired activator protein binding was obtained by purifying Hex A from KL urine and demonstrating a greater than 50% reduction of
in vitroG
M2hydrolysis compared to normal urinary Hex A. In other cDNA species (Type II), a maternally inherited
1367A ➡ C mutation converted
456Tyr ➡ Ser in another highly conserved region of the β-chain and we propose that this mutation leads to the inability of the β-chains to self associate and thus reach maturity. These same cDNA species contained a second
362A ➡ G mutation which converted
121Lys ➡ Arg, but is apparently a polymorphism since it also occurs in some normal subjects. We propose that the patient is a compound heterozygote in which a combination of no self-association of the mutant β-chains and impaired activator protein binding to α-β
(mutant)(Hex A) required for G
M2hydrolysis result in total β-Hex B deficiency and slow accumulation of G
M2ganglioside, primarily in motor neurons.
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Details
- Title
- Molecular basis of an adult form of β-hexosaminidase B deficiency with motor neuron disease
- Creators
- Probal Banerjee - The Joseph P. Kennedy, Jr. Mental Retardation Research Center, Departments of Pediatrics, Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USALuisa Siciliano - The Joseph P. Kennedy, Jr. Mental Retardation Research Center, Departments of Pediatrics, Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USADouglas Oliveri - The Joseph P. Kennedy, Jr. Mental Retardation Research Center, Departments of Pediatrics, Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USANorah R McCabe - The Joseph P. Kennedy, Jr. Mental Retardation Research Center, Departments of Pediatrics, Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USAMichael J Boyers - The Joseph P. Kennedy, Jr. Mental Retardation Research Center, Departments of Pediatrics, Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USAAllen L Horwitz - The Joseph P. Kennedy, Jr. Mental Retardation Research Center, Departments of Pediatrics, Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USASu-Chen Li - Dept. Biochemistry, Tulane University School of Medicine, New Orleans, LA 70112, USAGlyn Dawson - The Joseph P. Kennedy, Jr. Mental Retardation Research Center, Departments of Pediatrics, Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA
- Publication Details
- Biochemical and biophysical research communications, Vol.181(1), pp.108-115
- Academic Unit
- Molecular Biosciences, School of
- Publisher
- Elsevier Inc
- Identifiers
- 99900546710401842
- Language
- English
- Resource Type
- Journal article