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
Abstract 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 vari...
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| Format: | Article |
| Language: | English |
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BMC
2020-07-01
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| Series: | BMC Medical Genetics |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12881-020-01091-1 |
| _version_ | 1818612143221637120 |
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| author | Ingrid Bader Nina McTiernan Christine Darbakk Eugen Boltshauser Rasmus Ree Sabine Ebner Johannes A. Mayr Thomas Arnesen |
| author_facet | Ingrid Bader Nina McTiernan Christine Darbakk Eugen Boltshauser Rasmus Ree Sabine Ebner Johannes A. Mayr Thomas Arnesen |
| author_sort | Ingrid Bader |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-16T15:41:32Z |
| format | Article |
| id | doaj.art-27b4b3c30e91454e8be7e2d1f8050d7b |
| institution | Directory Open Access Journal |
| issn | 1471-2350 |
| language | English |
| last_indexed | 2024-12-16T15:41:32Z |
| publishDate | 2020-07-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medical Genetics |
| spelling | doaj.art-27b4b3c30e91454e8be7e2d1f8050d7b2022-12-21T22:25:58ZengBMCBMC Medical Genetics1471-23502020-07-012111910.1186/s12881-020-01091-1Severe syndromic ID and skewed X-inactivation in a girl with NAA10 dysfunction and a novel heterozygous de novo NAA10 p.(His16Pro) variant - a case reportIngrid Bader0Nina McTiernan1Christine Darbakk2Eugen Boltshauser3Rasmus Ree4Sabine Ebner5Johannes A. Mayr6Thomas Arnesen7Einheit für Klinische Genetik, Universitätsklinik für Kinder- und Jugendheilkunde, Paracelsus Medizinische UniversitätDepartment of Biomedicine, University of BergenDepartment of Biomedicine, University of BergenChildren’s University HospitalDepartment of Biomedicine, University of BergenEinheit für Klinische Genetik, Universitätsklinik für Kinder- und Jugendheilkunde, Paracelsus Medizinische UniversitätChildren’s Hospital, Paracelsus Medical UniversityDepartment of Biomedicine, University of BergenAbstract 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.http://link.springer.com/article/10.1186/s12881-020-01091-1NAA10X-linked intellectual disability (XLID)N-alpha-acetyltransferaseAcetylationNatACase report |
| spellingShingle | Ingrid Bader Nina McTiernan Christine Darbakk Eugen Boltshauser Rasmus Ree Sabine Ebner Johannes A. Mayr Thomas Arnesen 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 BMC Medical Genetics NAA10 X-linked intellectual disability (XLID) N-alpha-acetyltransferase Acetylation NatA Case report |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | NAA10 X-linked intellectual disability (XLID) N-alpha-acetyltransferase Acetylation NatA Case report |
| url | http://link.springer.com/article/10.1186/s12881-020-01091-1 |
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