Biochemical and molecular characterization of mutant hexosaminidase A in a Turkish family

Sinici, İncilay; Özkara, Hatice Asuman; Topçu, Meral; Ciliv, G

doi:10.1046/j.1442-200x.2003.01669.x

Cited by 5 publications

(2 citation statements)

References 21 publications

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“…To date, five infantile homozygote Turkish Tay-Sachs patients have been reported carrying a 12 bp deletion mutation in the α-subunit gene of Hex (Özkara et al 1998;Sinici et al 2003). The deletion mutation in exon 10 seems to be the most frequent Tay-Sachs mutation in Turkey and also the only mutation so far localized to exon 10.…”

Section: Discussionmentioning

confidence: 96%

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Assessing the severity of the small inframe deletion mutation in the α‐subunit of β‐hexosaminidase A found in the Turkish population by reproducing it in the more stable β‐subunit

Sinici

Tropak

Mahuran

et al. 2004

J of Inher Metab Disea

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SummaryGM 2 gangliosidoses are a group of panethnic lysosomal storage diseases in which GM 2 ganglioside accumulates in the lysosome due to a defect in one of three genes, two of which encode the α-or β-subunits of β-N-acetylhexosaminidase (Hex) A. A small inframe deletion mutation in the catalytic domain of the α-subunit of Hex has been found in five Turkish patients with infantile Tay-Sachs disease. To date it has not been detected in other populations and is the only mutation to be found in exon 10. It results in detectable levels of inactive α-protein in its precursor form. Because the α-and β-subunits share 60% sequence identity, the Hex A and Hex B genes are believed to have arisen from a common ancestral gene. Thus the subunits must share very similar three-dimensional structures with conserved functional domains. Hex B, the β-subunit homodimer is more stable than the heterodimeric Hex A, and much more stable than Hex S, the α homodimer. Thus, mutations that completely destabilize the α-subunit can often be partially rescued if expressed in the aligned positions in the β-subunit. To better understand the severity of the Turkish HEXA mutation, we reproduced the 12 bp deletion mutation (1267-1278) in the β-subunit cDNA. Western blot analysis of permanently transfected CHO cells expressing the mutant detected only the pro-form of the β-subunit coupled with a total lack of detectable Hex B activity. These data indicate that the deletion of the four amino acids severely affects the folding of even the more stable β-subunit, causing its retention in the endoplasmic reticulum and ultimate degradation.

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Section: Discussionmentioning

confidence: 96%

“…Previously, a 12 bp deletion mutation in the catalytic domain of the α-subunit of Hex A was found in five Turkish patients with infantile Tay-Sachs disease (Özkara and Navon 1998;Sinici et al 2003). It has not been documented in other populations and is the only mutation found in exon 10 to date.…”

Section: Introductionmentioning

confidence: 97%