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Pregled bibliografske jedinice broj: 380033

S-Adenosylhomocysteine hydrolase (AHCY) deficiency: Two novel mutations with lethal outcome


Vugrek, Oliver; Belužić, Robert; Nakić, Nikolina; Mudd, S. Harvey
S-Adenosylhomocysteine hydrolase (AHCY) deficiency: Two novel mutations with lethal outcome // Human mutation, 30 (2009), 4; E555-E565 doi:10.1002/humu.20985 (međunarodna recenzija, članak, znanstveni)


CROSBI ID: 380033 Za ispravke kontaktirajte CROSBI podršku putem web obrasca

Naslov
S-Adenosylhomocysteine hydrolase (AHCY) deficiency: Two novel mutations with lethal outcome

Autori
Vugrek, Oliver ; Belužić, Robert ; Nakić, Nikolina ; Mudd, S. Harvey

Izvornik
Human mutation (1059-7794) 30 (2009), 4; E555-E565

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
intermolecular disulphide bond ; NADH accumulation ; genotype-phenotype ; AHCY

Sažetak
This paper reports studies of two novel, allelic missense mutations found in the S-adenosylhomocysteine hydrolase (AHCY) gene from a new case of AHCY deficiency in an infant girl who died at age four months. The mutations lead to replacement of arginine with cysteine (p.Arg49Cys) and aspartic acid with glycine (p.Asp86Gly). Functional analysis of recombinant proteins containing the mutations detected showed that both dramatically reduce AHCY activity. The p.Arg49Cys mutant protein forms intermolecular disulphide bonds, leading to macromolecular structures that can be prevented by reducing agent DTT. The p.Asp86Gly protein tends to form enzymatically inactive aggregates and the loss of a single negative charge as a result of the mutation is involved in enzyme inactivation. We show that replacing Gly86 with negatively charged Glu86 in mutant protein restores enzymatic activity to 70% of wild-type, whereas changing Gly86 to positively charged Lys86 or uncharged Leu86 does not improve enzyme activity, indicating that the negative charge is important for maintenance of such activity. These studies significantly extend knowledge about the importance of residue 86 for AHCY activity. Residue 86 has not been implicated before in this way and the results suggest that the present model of S- adenosylhomocysteine (SAH) hydrolysis may need refinement. Our functional studies provide novel insight into the molecular defect underlying AHCY deficiency and reveal that both low enzyme activity and protein stability of AHCY contribute to the clinical phenotype.

Izvorni jezik
Engleski



POVEZANOST RADA


Projekti:
098-0000000-2463 - Nedostatak Adenozilhomocistein hidrolaze: Molekularni mehanizmi novog oboljenja (Vugrek, Oliver, MZOS ) ( POIROT)
108-1081870-1885 - Nasljedne metaboličke i ostale monogenske bolesti djece (Barić, Ivo, MZOS ) ( POIROT)

Ustanove:
Institut "Ruđer Bošković", Zagreb

Profili:

Avatar Url Robert Belužić (autor)

Avatar Url Nikolina Nakić (autor)

Avatar Url Oliver Vugrek (autor)

Citiraj ovu publikaciju

Vugrek, Oliver; Belužić, Robert; Nakić, Nikolina; Mudd, S. Harvey
S-Adenosylhomocysteine hydrolase (AHCY) deficiency: Two novel mutations with lethal outcome // Human mutation, 30 (2009), 4; E555-E565 doi:10.1002/humu.20985 (međunarodna recenzija, članak, znanstveni)
Vugrek, O., Belužić, R., Nakić, N. & Mudd, S. (2009) S-Adenosylhomocysteine hydrolase (AHCY) deficiency: Two novel mutations with lethal outcome. Human mutation, 30 (4), E555-E565 doi:10.1002/humu.20985.
@article{article, year = {2009}, pages = {E555-E565}, DOI = {10.1002/humu.20985}, keywords = {intermolecular disulphide bond, NADH accumulation, genotype-phenotype, AHCY}, journal = {Human mutation}, doi = {10.1002/humu.20985}, volume = {30}, number = {4}, issn = {1059-7794}, title = {S-Adenosylhomocysteine hydrolase (AHCY) deficiency: Two novel mutations with lethal outcome}, keyword = {intermolecular disulphide bond, NADH accumulation, genotype-phenotype, AHCY} }
@article{article, year = {2009}, pages = {E555-E565}, DOI = {10.1002/humu.20985}, keywords = {intermolecular disulphide bond, NADH accumulation, genotype-phenotype, AHCY}, journal = {Human mutation}, doi = {10.1002/humu.20985}, volume = {30}, number = {4}, issn = {1059-7794}, title = {S-Adenosylhomocysteine hydrolase (AHCY) deficiency: Two novel mutations with lethal outcome}, keyword = {intermolecular disulphide bond, NADH accumulation, genotype-phenotype, AHCY} }

Časopis indeksira:


  • Current Contents Connect (CCC)
  • Web of Science Core Collection (WoSCC)
    • Science Citation Index Expanded (SCI-EXP)
    • SCI-EXP, SSCI i/ili A&HCI
  • Scopus
  • MEDLINE


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