Pyruvate dehydrogenase deficiency: The relation of the E1⍺ mutation to the E1β subunit deficiency - 11/09/11

Doi : 10.1016/0887-8994(96)00058-6

Tatsuya Fujii, MD, PhD ^†,^{^{The authors acknowledge the technical contribution of Barbara Garity and comments and suggestions of Dr. Ruth M. Gubits.}}, Marcela B. Garcia Alvarez, MD ^†,^{^{The authors acknowledge the technical contribution of Barbara Garity and comments and suggestions of Dr. Ruth M. Gubits.}}, Kwan-Fu Rex Sheu, PhD ^‡,^{^{The authors acknowledge the technical contribution of Barbara Garity and comments and suggestions of Dr. Ruth M. Gubits.}}, Pamela J. Kranz-Eble, BS ^†,^{^{The authors acknowledge the technical contribution of Barbara Garity and comments and suggestions of Dr. Ruth M. Gubits.}}, Darryl C. De Vivo, MD ^⁎,^†,^{^{The authors acknowledge the technical contribution of Barbara Garity and comments and suggestions of Dr. Ruth M. Gubits.}}
^a Division of Pediatric Neurology; Department of Neurology; College of Physicians and Surgeons of Columbia University; New York, USA
^b Department of Neurology; Cornell Medical College at Burke Medical Research Institute; White Plains, New York, USA

Communications should be addressed to: Dr. De Vivo; Neurological Institute; 710 West 168th Street; New York, NY 10032 USA.

Abstract

We report 7 patients with pyruvate dehydrogenase (PDH) deficiency caused by mutations of the PDH-E1⍺ subunit. Each patient had a different mutation; 4 with duplicate insertions, 1 with a deletion of tandem repeat, and 2 with point mutations. Five of the mutations were novel, thus confirming allelic heterogeneity. Immunoblot analysis revealed decreased immunoreactivity for the E1⍺ and E1β subunits in every patient. Pulse-labeling and chase study of the E1⍺ and E1β subunits revealed that initial synthesis of the mutant E1⍺ subunit was normal and posttranslational degradation was complete by 48 hours. However, the post-translational degradation rate of the E1β subunit varied from one patient to another. Factors other than instability of the E1β monomer must contribute to the degradation rate of this subunit in the presence of an E1⍺ subunit mutation. Including this series, 3 patients with thhe S312 deletion and 5 with the R302C point mutation have been reported, and all of these patients are female. These findings suggest that these two loci are hot spots for gene mutations, and may be lethal in the male fetus.

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	Presented in part at the 23rd Annual Meeting of the Child Neurology Society, October 2–8, 1994, San Francisco, California (Ann Neurol 1994; 34:491).
	This work was supported by the Colleen Giblin Foundation for Pediatric Neurological Research.