A mutation common in non-Jewish Tay-Sachs disease: Frequency and RNA studies

B. R. Akerman, J. Zielenski, B. L. Triggs-Raine, E. M. Prence, M. R. Natowicz, J. S T Lim-Steele, M. M. Kaback, E. H. Mules, G. H. Thomas, J. T R Clarke, R. A. Gravel

Research output: Contribution to journalArticle

Abstract

Tay-Sachs disease (TSD) is an autosomal recessive genetic disorder resulting from mutation of the HEXA gene encoding the α-subunit of the lysosomal enzyme, β-N-acetylhexosaminidase A (Hex A). We have discovered that a Tay-Sachs mutation, IVS-9 + 1 G→A, first detected by Akli et al. (Genomics 11:124-134, 1991), is a common disease allele in non-Jewish Caucasians (10/58 alleles examined). A PCR-based diagnostic test, which detects an NlaIII site generated by the mutation, revealed a frequency among enzyme-defined carriers of 9/64 (14%). Most of those carrying the allele trace their origins to the United Kingdom, Ireland, or Western Europe. It was not identified among 12. Black American TSD alleles or in any of 18 Ashkenazi Jewish, enzyme-defined carriers who did not carry any of the mutations common to this population. No normally spliced RNA was detected in PCR products generated from reverse transcription of RNA carrying the IVS-9 mutation. Instead, the low levels of mRNA from this allele were comprised of aberrant species resulting from the use of either of two cryptic donor sites, one truncating exon 9 and the other within IVS-9, spliced to exon 10. Numerous additional splice products were detected, most involving skipping of one or more surrounding exons. Together with a recently identified allele responsible for Hex A pseudodeficiency (Triggs-Raine et al. Am J Hum Genet, 1992), these two alleles accounted for almost 50% (29/64) of TSD or carrier alleles ascertained by enzyme screening tests in non-Jewish Caucasians.

Original languageEnglish (US)
Pages (from-to)303-309
Number of pages7
JournalHuman Mutation
Volume1
Issue number4
StatePublished - 1992

Fingerprint

Tay-Sachs Disease
Alleles
RNA
Mutation
Hexosaminidase A
Exons
Enzymes
Viverridae
Polymerase Chain Reaction
Inborn Genetic Diseases
Genomics
Ireland
Routine Diagnostic Tests
Reverse Transcription
Messenger RNA

Keywords

  • β-hexosaminidase A
  • GM gangliosidosis
  • Hex A gene
  • Splicing

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Akerman, B. R., Zielenski, J., Triggs-Raine, B. L., Prence, E. M., Natowicz, M. R., Lim-Steele, J. S. T., ... Gravel, R. A. (1992). A mutation common in non-Jewish Tay-Sachs disease: Frequency and RNA studies. Human Mutation, 1(4), 303-309.

A mutation common in non-Jewish Tay-Sachs disease : Frequency and RNA studies. / Akerman, B. R.; Zielenski, J.; Triggs-Raine, B. L.; Prence, E. M.; Natowicz, M. R.; Lim-Steele, J. S T; Kaback, M. M.; Mules, E. H.; Thomas, G. H.; Clarke, J. T R; Gravel, R. A.

In: Human Mutation, Vol. 1, No. 4, 1992, p. 303-309.

Research output: Contribution to journalArticle

Akerman, BR, Zielenski, J, Triggs-Raine, BL, Prence, EM, Natowicz, MR, Lim-Steele, JST, Kaback, MM, Mules, EH, Thomas, GH, Clarke, JTR & Gravel, RA 1992, 'A mutation common in non-Jewish Tay-Sachs disease: Frequency and RNA studies', Human Mutation, vol. 1, no. 4, pp. 303-309.
Akerman BR, Zielenski J, Triggs-Raine BL, Prence EM, Natowicz MR, Lim-Steele JST et al. A mutation common in non-Jewish Tay-Sachs disease: Frequency and RNA studies. Human Mutation. 1992;1(4):303-309.
Akerman, B. R. ; Zielenski, J. ; Triggs-Raine, B. L. ; Prence, E. M. ; Natowicz, M. R. ; Lim-Steele, J. S T ; Kaback, M. M. ; Mules, E. H. ; Thomas, G. H. ; Clarke, J. T R ; Gravel, R. A. / A mutation common in non-Jewish Tay-Sachs disease : Frequency and RNA studies. In: Human Mutation. 1992 ; Vol. 1, No. 4. pp. 303-309.
@article{6abc5719c05e4573aa8e368ca1939fc5,
title = "A mutation common in non-Jewish Tay-Sachs disease: Frequency and RNA studies",
abstract = "Tay-Sachs disease (TSD) is an autosomal recessive genetic disorder resulting from mutation of the HEXA gene encoding the α-subunit of the lysosomal enzyme, β-N-acetylhexosaminidase A (Hex A). We have discovered that a Tay-Sachs mutation, IVS-9 + 1 G→A, first detected by Akli et al. (Genomics 11:124-134, 1991), is a common disease allele in non-Jewish Caucasians (10/58 alleles examined). A PCR-based diagnostic test, which detects an NlaIII site generated by the mutation, revealed a frequency among enzyme-defined carriers of 9/64 (14{\%}). Most of those carrying the allele trace their origins to the United Kingdom, Ireland, or Western Europe. It was not identified among 12. Black American TSD alleles or in any of 18 Ashkenazi Jewish, enzyme-defined carriers who did not carry any of the mutations common to this population. No normally spliced RNA was detected in PCR products generated from reverse transcription of RNA carrying the IVS-9 mutation. Instead, the low levels of mRNA from this allele were comprised of aberrant species resulting from the use of either of two cryptic donor sites, one truncating exon 9 and the other within IVS-9, spliced to exon 10. Numerous additional splice products were detected, most involving skipping of one or more surrounding exons. Together with a recently identified allele responsible for Hex A pseudodeficiency (Triggs-Raine et al. Am J Hum Genet, 1992), these two alleles accounted for almost 50{\%} (29/64) of TSD or carrier alleles ascertained by enzyme screening tests in non-Jewish Caucasians.",
keywords = "β-hexosaminidase A, GM gangliosidosis, Hex A gene, Splicing",
author = "Akerman, {B. R.} and J. Zielenski and Triggs-Raine, {B. L.} and Prence, {E. M.} and Natowicz, {M. R.} and Lim-Steele, {J. S T} and Kaback, {M. M.} and Mules, {E. H.} and Thomas, {G. H.} and Clarke, {J. T R} and Gravel, {R. A.}",
year = "1992",
language = "English (US)",
volume = "1",
pages = "303--309",
journal = "Human Mutation",
issn = "1059-7794",
publisher = "Wiley-Liss Inc.",
number = "4",

}

TY - JOUR

T1 - A mutation common in non-Jewish Tay-Sachs disease

T2 - Frequency and RNA studies

AU - Akerman, B. R.

AU - Zielenski, J.

AU - Triggs-Raine, B. L.

AU - Prence, E. M.

AU - Natowicz, M. R.

AU - Lim-Steele, J. S T

AU - Kaback, M. M.

AU - Mules, E. H.

AU - Thomas, G. H.

AU - Clarke, J. T R

AU - Gravel, R. A.

PY - 1992

Y1 - 1992

N2 - Tay-Sachs disease (TSD) is an autosomal recessive genetic disorder resulting from mutation of the HEXA gene encoding the α-subunit of the lysosomal enzyme, β-N-acetylhexosaminidase A (Hex A). We have discovered that a Tay-Sachs mutation, IVS-9 + 1 G→A, first detected by Akli et al. (Genomics 11:124-134, 1991), is a common disease allele in non-Jewish Caucasians (10/58 alleles examined). A PCR-based diagnostic test, which detects an NlaIII site generated by the mutation, revealed a frequency among enzyme-defined carriers of 9/64 (14%). Most of those carrying the allele trace their origins to the United Kingdom, Ireland, or Western Europe. It was not identified among 12. Black American TSD alleles or in any of 18 Ashkenazi Jewish, enzyme-defined carriers who did not carry any of the mutations common to this population. No normally spliced RNA was detected in PCR products generated from reverse transcription of RNA carrying the IVS-9 mutation. Instead, the low levels of mRNA from this allele were comprised of aberrant species resulting from the use of either of two cryptic donor sites, one truncating exon 9 and the other within IVS-9, spliced to exon 10. Numerous additional splice products were detected, most involving skipping of one or more surrounding exons. Together with a recently identified allele responsible for Hex A pseudodeficiency (Triggs-Raine et al. Am J Hum Genet, 1992), these two alleles accounted for almost 50% (29/64) of TSD or carrier alleles ascertained by enzyme screening tests in non-Jewish Caucasians.

AB - Tay-Sachs disease (TSD) is an autosomal recessive genetic disorder resulting from mutation of the HEXA gene encoding the α-subunit of the lysosomal enzyme, β-N-acetylhexosaminidase A (Hex A). We have discovered that a Tay-Sachs mutation, IVS-9 + 1 G→A, first detected by Akli et al. (Genomics 11:124-134, 1991), is a common disease allele in non-Jewish Caucasians (10/58 alleles examined). A PCR-based diagnostic test, which detects an NlaIII site generated by the mutation, revealed a frequency among enzyme-defined carriers of 9/64 (14%). Most of those carrying the allele trace their origins to the United Kingdom, Ireland, or Western Europe. It was not identified among 12. Black American TSD alleles or in any of 18 Ashkenazi Jewish, enzyme-defined carriers who did not carry any of the mutations common to this population. No normally spliced RNA was detected in PCR products generated from reverse transcription of RNA carrying the IVS-9 mutation. Instead, the low levels of mRNA from this allele were comprised of aberrant species resulting from the use of either of two cryptic donor sites, one truncating exon 9 and the other within IVS-9, spliced to exon 10. Numerous additional splice products were detected, most involving skipping of one or more surrounding exons. Together with a recently identified allele responsible for Hex A pseudodeficiency (Triggs-Raine et al. Am J Hum Genet, 1992), these two alleles accounted for almost 50% (29/64) of TSD or carrier alleles ascertained by enzyme screening tests in non-Jewish Caucasians.

KW - β-hexosaminidase A

KW - GM gangliosidosis

KW - Hex A gene

KW - Splicing

UR - http://www.scopus.com/inward/record.url?scp=12244260375&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=12244260375&partnerID=8YFLogxK

M3 - Article

C2 - 1301938

AN - SCOPUS:12244260375

VL - 1

SP - 303

EP - 309

JO - Human Mutation

JF - Human Mutation

SN - 1059-7794

IS - 4

ER -