Severe syndromic ID and skewed X-inactivation in a girl with NAA10 dysfunction and a novel heterozygous de novo NAA10 p.(His16Pro) variant - a case report.
Amino Acid Sequence
Biocatalysis
Child
Cycloheximide
/ metabolism
Female
HeLa Cells
Heterozygote
Humans
Intellectual Disability
/ genetics
Male
Mutation
/ genetics
N-Terminal Acetyltransferase A
/ chemistry
N-Terminal Acetyltransferase E
/ chemistry
Pedigree
Syndrome
X Chromosome Inactivation
/ genetics
Acetylation
Case report
N-alpha-acetyltransferase
NAA10
NatA
X-linked intellectual disability (XLID)
Journal
BMC medical genetics
ISSN: 1471-2350
Titre abrégé: BMC Med Genet
Pays: England
ID NLM: 100968552
Informations de publication
Date de publication:
22 07 2020
22 07 2020
Historique:
received:
31
03
2020
accepted:
12
07
2020
entrez:
24
7
2020
pubmed:
24
7
2020
medline:
29
10
2020
Statut:
epublish
Résumé
NAA10 is the catalytic subunit of the major N-terminal acetyltransferase complex NatA which acetylates almost half the human proteome. Over the past decade, many NAA10 missense variants have been reported as causative of genetic disease in humans. Individuals harboring NAA10 variants often display variable degrees of intellectual disability (ID), developmental delay, and cardiac anomalies. Initially, carrier females appeared to be oligo- or asymptomatic with X-inactivation pattern skewed towards the wild type allele. However, recently it has been shown that NAA10 variants can cause syndromic or non-syndromic intellectual disability in females as well. The impact of specific NAA10 variants and the X-inactivation pattern on the individual phenotype in females remains to be elucidated. Here we present a novel de novo NAA10 (NM_003491.3) c.[47A > C];[=] (p.[His16Pro];[=]) variant identified in a young female. The 10-year-old girl has severely delayed motor and language development, disturbed behavior with hyperactivity and restlessness, moderate dilatation of the ventricular system and extracerebral CSF spaces. Her blood leukocyte X-inactivation pattern was skewed (95/5) towards the maternally inherited X-chromosome. Our functional study indicates that NAA10 p.(H16P) impairs NatA complex formation and NatA catalytic activity, while monomeric NAA10 catalytic activity appears to be intact. Furthermore, cycloheximide experiments show that the NAA10 H16P variant does not affect the cellular stability of NAA10. We demonstrate that NAA10 p.(His16Pro) causes a severe form of syndromic ID in a girl most likely through impaired NatA-mediated Nt-acetylation of cellular proteins. X-inactivation analyses showed a skewed X-inactivation pattern in DNA from blood of the patient with the maternally inherited allele being preferentially methylated/inactivated.
Sections du résumé
BACKGROUND
NAA10 is the catalytic subunit of the major N-terminal acetyltransferase complex NatA which acetylates almost half the human proteome. Over the past decade, many NAA10 missense variants have been reported as causative of genetic disease in humans. Individuals harboring NAA10 variants often display variable degrees of intellectual disability (ID), developmental delay, and cardiac anomalies. Initially, carrier females appeared to be oligo- or asymptomatic with X-inactivation pattern skewed towards the wild type allele. However, recently it has been shown that NAA10 variants can cause syndromic or non-syndromic intellectual disability in females as well. The impact of specific NAA10 variants and the X-inactivation pattern on the individual phenotype in females remains to be elucidated.
CASE PRESENTATION
Here we present a novel de novo NAA10 (NM_003491.3) c.[47A > C];[=] (p.[His16Pro];[=]) variant identified in a young female. The 10-year-old girl has severely delayed motor and language development, disturbed behavior with hyperactivity and restlessness, moderate dilatation of the ventricular system and extracerebral CSF spaces. Her blood leukocyte X-inactivation pattern was skewed (95/5) towards the maternally inherited X-chromosome. Our functional study indicates that NAA10 p.(H16P) impairs NatA complex formation and NatA catalytic activity, while monomeric NAA10 catalytic activity appears to be intact. Furthermore, cycloheximide experiments show that the NAA10 H16P variant does not affect the cellular stability of NAA10.
DISCUSSION AND CONCLUSIONS
We demonstrate that NAA10 p.(His16Pro) causes a severe form of syndromic ID in a girl most likely through impaired NatA-mediated Nt-acetylation of cellular proteins. X-inactivation analyses showed a skewed X-inactivation pattern in DNA from blood of the patient with the maternally inherited allele being preferentially methylated/inactivated.
Identifiants
pubmed: 32698785
doi: 10.1186/s12881-020-01091-1
pii: 10.1186/s12881-020-01091-1
pmc: PMC7374887
doi:
Substances chimiques
Cycloheximide
98600C0908
N-Terminal Acetyltransferase A
EC 2.3.1.254
NAA10 protein, human
EC 2.3.1.255
N-Terminal Acetyltransferase E
EC 2.3.1.258
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
153Subventions
Organisme : Austrian Science Fund FWF
ID : I 2741
Pays : Austria
Organisme : ERA-Net E-Rare project GENOMIT
ID : FWF I 2741-B26
Pays : International
Organisme : Norwegian Health Authorities of Western Norway
ID : 912176
Pays : International
Organisme : Research Council of Norway
ID : 249843
Pays : International
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