Nonaka myopathy is caused by mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase gene (GNE)

Abstract

This is the first report on mutations of the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase gene (GNE) in Nonaka myopathy or distal myopathy with rimmed vacuoles (OMIM 605820), an autosomal recessive neuromuscular disorder. Sequence and haplotype analyses of GNE in two siblings with Nonaka myopathy from a Japanese family revealed that both patients were compound heterozygotes for a CAET transition (A460V) in exon 8 and a GAEC transition (V572L) in exon 10. Their parents and a normal elder brother were all carriers for one or the other of the mutations. GNE mutations are known to cause two other disorders: sialuria (OMIM #269921) and autosomal recessive inclusion body myopathy (IBM2, OMIM #600737). Mutations associated with sialuria are located in the epimerase domain, and those associated with IBM2 are in the epimerase or the kinase domain or both, whereas the mutations we observed in the Nonaka myopathy patients were located in the sugar kinase domain of the gene. Thus, Nonaka myopathy is the third disease known to be caused by GNE mutations.

Lec3 Chinese Hamster Ovary Mutants Lack UDP-N-acetylglucosamine 2-Epimerase Activity Because of Mutations in the Epimerase Domain of the Gne Gene

“…Briefly, 2 l of total RNA (1 ϫ 10 6 cell equivalents) from CHO or Lec3 cells were mixed with 1 l of 500 g/ml oligo dT [12][13][14][15][16][17][18] primer, 1 l of 10 mM dNTP, and 8 l of water and incubated at 65°C for 5 min. After cooling on ice, 4 l of 5ϫ first strand buffer, 4 l of 0.1 M dithiothreitol, and 1 l of RNA OUT were mixed and incubated at 42°C for 2 min.…”

“…In conclusion, Lec3 CHO mutants are well suited for fundamental studies of mutations that alter UDP-GlcNAc 2-epimerase activity including human GNE mutations that cause sialuria and the myopathic disorders, HIBM and Nonaka myopathy (13,14,44 …”

“…Point mutations at allosteric sites in the epimerase domain are the cause of sialuria in which patients lose feedback control by CMP-Neu5Ac and secrete large amounts of sialic acid in their urine (12). The loss of epimerase or kinase activities also induces aberrations of muscular motility that are the cause of HIBM or Nonaka myopathy (13,14). To generate sialic acid, ManNAc-6-phosphate is condensed with phosphoenolpyruvate to form Neu5Ac-9-phosphate by sialic acid synthase (15).…”

Characterization of the Substrate Specificity of Human Carboxypeptidase A4 and Implications for a Role in Extracellular Peptide Processing

“…The human CPA4 gene is located on chromosome 7q32, which is a region in the genome that might contain genes for prostate cancer aggressiveness (10). In addition, the CPA4 gene was found to be maternally imprinted in a tissue-specific manner (11,12). Furthermore, imprinting in adult benign hypertrophic prostate tissue suggests that mutations or aberrant imprinting in CPA4 may be related to prostate cancer aggressiveness (12).…”

“…In addition, the CPA4 gene was found to be maternally imprinted in a tissue-specific manner (11,12). Furthermore, imprinting in adult benign hypertrophic prostate tissue suggests that mutations or aberrant imprinting in CPA4 may be related to prostate cancer aggressiveness (12). Ross et al (13) studied the association of single-nucleotide polymorphisms on the CPA4 gene and its relation to prostate cancer and found that the nonsynonymous coding single-nucleotide polymorphism (G303C) rs2171492 was associated with an increased risk of aggressive disease in younger men.…”