{'fraction_non_alphanumeric': 0.037941787941787944, 'fraction_numerical': 0.030145530145530147, 'mean_word_length': 5.481481481481482, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
W474C amino acid substitution affects early processing of the α‐subunit of β‐hexosaminidase A and is associated with subacute GM2 gangliosidosis

Mutations in the HEXA gene, encoding the α‐subunit of β‐hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay‐Sachs disease (TSD), the fatal infantile form of GM2 gangliosidosis, Type 1. Less severe, subacute (juvenile‐onset) and chronic (adult‐onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G→C (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non‐Jewish proband who manifested a subacute variant of GM2 gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease‐causing 4‐bp insertion, +TATC 1278, in exon 11. Pulse‐chase analysis using proband fibroblasts revealed that the W474C‐containing α‐subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal α‐subunit was not detected. When the W474C‐containing α‐subunit was transiently co‐expressed with the β‐subunit to produce Hex A (αβ) in COS‐7 cells, the mature α‐subunit was present, but its level was much lower than that from normal α‐subunit transfections, although higher than in those cells transfected with an α‐subunit associated with infantile TSD. Furthermore, the precursor level of the W474C α‐subunit was found to accumulate in comparison to the normal α‐subunit precursor levels. We conclude that the 1422 G→C mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with α‐subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband. Hum Mutat 11:432–442, 1998. © 1998 Wiley‐Liss, Inc.