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Biochemical and cellular analysis of Ogden syndrome reveals downstream Nt-acetylation defects.

ABSTRACT: The X-linked lethal Ogden syndrome was the first reported human genetic disorder associated with a mutation in an N-terminal acetyltransferase (NAT) gene. The affected males harbor an Ser37Pro (S37P) mutation in the gene encoding Naa10, the catalytic subunit of NatA, the major human NAT involved in the co-translational acetylation of proteins. Structural models and molecular dynamics simulations of the human NatA and its S37P mutant highlight differences in regions involved in catalysis and at the interface between Naa10 and the auxiliary subunit hNaa15. Biochemical data further demonstrate a reduced catalytic capacity and an impaired interaction between hNaa10 S37P and Naa15 as well as Naa50 (NatE), another interactor of the NatA complex. N-Terminal acetylome analyses revealed a decreased acetylation of a subset of NatA and NatE substrates in Ogden syndrome cells, supporting the genetic findings and our hypothesis regarding reduced Nt-acetylation of a subset of NatA/NatE-type substrates as one etiology for Ogden syndrome. Furthermore, Ogden syndrome fibroblasts display abnormal cell migration and proliferation capacity, possibly linked to a perturbed retinoblastoma pathway. N-Terminal acetylation clearly plays a role in Ogden syndrome, thus revealing the in vivo importance of N-terminal acetylation in human physiology and disease.

SUBMITTER: Myklebust LM

PROVIDER: S-EPMC4355026 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Biochemical and cellular analysis of Ogden syndrome reveals downstream Nt-acetylation defects.

Myklebust Line M LM Van Damme Petra P Støve Svein I SI Dörfel Max J MJ Abboud Angèle A Kalvik Thomas V TV Grauffel Cedric C Jonckheere Veronique V Wu Yiyang Y Swensen Jeffrey J Kaasa Hanna H Liszczak Glen G Marmorstein Ronen R Reuter Nathalie N Lyon Gholson J GJ Gevaert Kris K Arnesen Thomas T

Human molecular genetics 20141208 7

The X-linked lethal Ogden syndrome was the first reported human genetic disorder associated with a mutation in an N-terminal acetyltransferase (NAT) gene. The affected males harbor an Ser37Pro (S37P) mutation in the gene encoding Naa10, the catalytic subunit of NatA, the major human NAT involved in the co-translational acetylation of proteins. Structural models and molecular dynamics simulations of the human NatA and its S37P mutant highlight differences in regions involved in catalysis and at t ...[more]

PMID: 25489052

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Project description:N-terminal acetylation (Nt-acetylation) occurs on the majority of eukaryotic proteins and is catalyzed by N-terminal acetyltransferases (NATs). Nt-acetylation is increasingly recognized as a vital modification with functional implications ranging from protein degradation to protein localization. Although early genetic studies in yeast demonstrated that NAT-deletion strains displayed a variety of phenotypes, only recently, the first human genetic disorder caused by a mutation in a NAT gene was reported; boys diagnosed with the X-linked Ogden syndrome harbor a p.Ser37Pro (S37P) mutation in the gene encoding Naa10, the catalytic subunit of the NatA complex, and suffer from global developmental delays and lethality during infancy. Here, we describe a Saccharomyces cerevisiae model developed by introducing the human wild-type or mutant NatA complex into yeast lacking NatA (NatA-?). The wild-type human NatA complex phenotypically complemented the NatA-? strain, whereas only a partial rescue was observed for the Ogden mutant NatA complex suggesting that hNaa10 S37P is only partially functional in vivo. Immunoprecipitation experiments revealed a reduced subunit complexation for the mutant hNatA S37P next to a reduced in vitro catalytic activity. We performed quantitative Nt-acetylome analyses on a control yeast strain (yNatA), a yeast NatA deletion strain (yNatA-?), a yeast NatA deletion strain expressing wild-type human NatA (hNatA), and a yeast NatA deletion strain expressing mutant human NatA (hNatA S37P). Interestingly, a generally reduced degree of Nt-acetylation was observed among a large group of NatA substrates in the yeast expressing mutant hNatA as compared with yeast expressing wild-type hNatA. Combined, these data provide strong support for the functional impairment of hNaa10 S37P in vivo and suggest that reduced Nt-acetylation of one or more target substrates contributes to the pathogenesis of the Ogden syndrome. Comparative analysis between human and yeast NatA also provided new insights into the co-evolution of the NatA complexes and their substrates. For instance, (Met-)Ala- N termini are more prevalent in the human proteome as compared with the yeast proteome, and hNatA displays a preference toward these N termini as compared with yNatA.

Project description:Introduction: The definition of ultra-rare disease in terms of its prevalence varies between the sources, usually amounting to ca. 1 in 1.000.000 births. Nonetheless, there are even less frequent disorders, such as Ogden syndrome, which up to this day was diagnosed in less than 10 patients worldwide. They present typically with a variety of developmental defects, including postnatal growth retardation, psychomotor delay and hypotonia. This disorder is caused by the heterozygous mutations in NAA10 gene, which encodes N-alpha-acetyltransferase 10, involved in protein biosynthesis. Therefore, Ogden syndrome belongs to the broader group of genetic disorders, collectively described as NAA10-related syndrome. Case report: We present a case of a Polish male infant, born in 39. GW with c-section due to the pathological cardiotocography signal. Hypotrophy (2400 g) and facial dysmorphism were noted in the physical examination. From the first minute, the child required mechanical ventilation - a nasal continuous positive airway pressure. For the first 27 days, the patient was treated in a neonatal intensive care unit, where a series of examinations were conducted. On their basis, the presence of the following defects was determined: muscular ventricular septal defects, patent foramen ovale, pectus excavatum, clubfoot and axial hypotonia. Child was then consequently referred to the genetic clinic for counselling. Results of the tests allowed the diagnosis of Ogden syndrome. In the following months the patient's condition worsened due to the numerous pulmonary infections. Despite the advanced treatment including the variety of medications, the patient eventually died at the age of 10 months. Conclusion: This case report presents a tenth patient diagnosed with Ogden syndrome reported worldwide. It expands the morphologic and clinical phenotype, emphasizing the possible severity of pneumonological disorders in these patients, which may pose a greater threat to a child's life than more frequently described cardiovascular dysfunctions associated with this syndrome.

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Biochemical and cellular analysis of Ogden syndrome reveals downstream Nt-acetylation defects.

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Biochemical and cellular analysis of Ogden syndrome reveals downstream Nt-acetylation defects.

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