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Pedigree of family affected with Lenz microphthalmia syndrome (LMS), supporting clinical features, and con fi rmation by Sanger sequencing. (A) Pedigree of LMS affected family. Further experimentation and analyses focused on the three living affected brothers (VI-9, VI-10, VI-11), one obligate heterozygote (V-10), one heterozygote identi fi ed previously by linkage (V-6) and her daughter (VI-4). Analysis of family pedigree was consistent with sex-linked inheritance. (B) Bilateral anophthalmia is an example of a dysmorphic feature present in patients affected by LMS (VI-9). (C) Haematoxylin and eosin staining of skeletal muscle showing neuropathic degeneration (arrow). (D) Dysmorphic features such as cutaneous syndactyly between the second and third toes and short terminal phalanges are present in a heterozygote (V-10). (E) Sanger sequencing of NAA10 gene (genomic DNA) shows the c.471+2T → A mutation present in all three affected males (VI-9, VI-10, VI-11), their obligate heterozygote mother (V-10), as well as an aunt who was previously suspected as a heterozygote by linkage (V-6) and one of her daughters (VI-4).
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Lenz microphthalmia syndrome (LMS) is a genetically heterogeneous X-linked disorder characterised by microphthalmia/anophthalmia, skeletal abnormalities, genitourinary malformations, and anomalies of the digits, ears, and teeth. Intellectual disability and seizure disorders are seen in about 60% of affected males. To date, no gene has been identifi...
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... on the LOD score, MCOPS2 (Xpter-Xq24) was not likely linked. 4 The updated pedigree and clinical information are shown in figure 1A. ...
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... recently updated pedigree information included seven gen- erations with a total of 10 participants in this family of mixed European descent, including German, Italian, and other north- ern European backgrounds ( figure 1A). Analysis of the pedigree was consistent with X-linked inheritance. ...
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... has not developed words, and relies completely on sign lan- guage. In addition, haematoxylin and eosin (H&E) staining of his skeletal muscle showed muscle degeneration ( figure 1C). He also required surgical intervention to lengthen his heel cord. ...
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... heterozygotes (VI-4, V-6, V-10) had cutaneous syndac- tyly between the second and third toes and short terminal pha- langes ( figure 1D). These manifestations were not seen in the individual without the mutation. ...
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... variant predicts a mutation at the intron 7 GT splice donor site (c.471+2T→A) of NAA10. The NAA10 splice mutation was confirmed via Sanger sequencing in all three affected males (VI-9, VI-10, VI-11), their obligate heterozygote mother (V-10), as well as an aunt who was previously suspected as a heterozygote by linkage (V-6) and one of her daughters (VI-4) ( figure 1E). NAA10 is in Xq27, but was not inside the region previously defined by DXS1232 and DXS8043 markers. ...
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... is in Xq27, but was not inside the region previously defined by DXS1232 and DXS8043 markers. This may be the reason why no mutations were detected when sequencing the genes within these markers in the study by Forrester et al. 4 The NAA10 c.471+2T>A muta- tion was not found in any of the four unaffected individuals in this family (V-8, VI-5, VI-6, VI-12) ( figure 1E). Therefore, the mutation segregated with the disease in this pedigree. ...
Citations
... Since the initial discovery of OS in 2011, multiple groups have reported additional variants either in NAA10 in both males and females [33][34][35][36][37][38][39][40][41][42][43][44][45][46] or in the heterodimeric protein partner encoded by NAA15 [35,[47][48][49][50]. The genetic landscape of variation in NAA10 and NAA15 in humans has been presented recently with many more cases of Ogden syndrome (OS) (also known as "NAA10-related neurodevelopmental syndrome"), and "NAA15-related neurodevelopmental syndrome" [51]. ...
Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting approximately 80% of all human proteins. The human essential X-linked gene, NAA10 , encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex. There is extensive genetic variation in humans with missense, splice-site, and C-terminal frameshift variants in NAA10 . In mice, Naa10 is not an essential gene, as there exists a paralogous gene, Naa12 , that substantially rescues Naa10 knockout mice from embryonic lethality, whereas double knockouts ( Naa10 -/Y Naa12 -/-) are embryonic lethal. However, the phenotypic variability in the mice is nonetheless quite extensive, including piebaldism, skeletal defects, small size, hydrocephaly, hydronephrosis, and neonatal lethality. Here we replicate these phenotypes with new genetic alleles in mice, but we demonstrate their modulation by genetic background and environmental effects. We cannot replicate a prior report of "maternal effect lethality" for heterozygous Naa10 -/X female mice, but we do observe a small amount of embryonic lethality in the Naa10 -/y male mice on the inbred genetic background in this different animal facility.
... Additionally, the severity depends on the specific pathogenic variant leading to the disease and individual sex as males tend to show more severe symptoms than their female counterparts 15 . Along the spectrum of associated manifestations, there are several cardiac, central nervous system, anatomical, and developmental abnormalities which depend upon the sex and pathogenic variant type for their specific presentation 1,[14][15][16][17][18][19][20][20][21][22][23][24][25][26]28,37,41 . Specific brain abnormalities that have been associated with Ogden syndrome include enlarged ventricles, cerebral dysgenesis, and seizures 15 . ...
Ogden syndrome, also known as NAA10-related neurodevelopmental syndrome, is a rare genetic condition associated with pathogenic variants in the NAA10 N-terminal acetylation family of proteins. The condition was initially described in 2011, and is characterized by a range of neurologic symptoms, including intellectual disability and seizures, as well as developmental delays, psychiatric symptoms, congenital heart abnormalities, hypotonia and others. Previously published articles have described the etiology and phenotype of Ogden syndrome, mostly with retrospective analyses; herein, we report prospective data concerning its progress over time. Additionally, we describe the nature of seizures in this condition in greater detail, as well as investigate how already-available non-pharmaceutical therapies impact individuals with NAA10-related neurodevelopmental syndrome. Using Vineland-3 scores, we show decline in cognitive function over time in individuals with Ogden syndrome. Sub-domain analysis found the decline to be present across all modalities. Additional investigation between seizure and non-seizure groups showed no significant difference in adaptive behavior outcomes. Therapy investigation showed speech therapy to be the most commonly used therapy by individuals with NAA10-related neurodevelopmental syndrome, followed by occupational and physical therapy. with more severely affected individuals receiving more types of therapy than their less-severe counterparts. Early intervention analysis was only significantly effective for speech therapy, with analyses of all other therapies being non-significant. Our study portrays the decline in cognitive function over time of individuals within our cohort, independent of seizure status and therapies being received, and highlights the urgent need for the development of effective treatments for Ogden syndrome.
... Since then, there have been other NAA10 and NAA15 variants that have been identified with their phenotypic manifestations, including variable degrees of intellectual disability, hypotonia, congenital cardiac abnormalities, seizures, and delayed speech and motor development [6][7][8][9][10][11][12][13][14][15][16] . A large subset of individuals with NAA10, and to a lesser extent NAA15, mutations also present with visual abnormalities, including myopia, astigmatism, and cortical visual impairment (CVI) 7 . ...
... Mutations in the NAA10 and NAA15 genes affect the development of multiple organ systems, including the eyes 11,12,15 . Literature on NAA10-and NAA15-related neurodevelopmental syndromes to date has not focused on the specifics of ophthalmologic manifestations in a large cohort. ...
... The specific function of NAA10 and NAA15 in visual system development are not fully clear. Previous literature has suggested that NAA10 may be involved in retinoic acid signaling, which is critical for ocular development 12,24 . The critical role of NAA10 in eye development was further supported by a study on zebrafish, wherein NAA10 knockdowns produced small, underdeveloped eyes 25 . ...
NAA10-related and NAA15-related neurodevelopmental syndrome, otherwise known as Ogden Syndrome, is known to present with varying degrees of intellectual disability, hypotonia, congenital cardiac abnormalities, seizures, and delayed speech and motor development. However, the ophthalmic manifestations of NAA10 and NAA15 mutations are not yet fully characterized or understood. This study analyzed the prevalence of six ophthalmic conditions (cortical visual impairment, myopia, hyperopia, strabismus, nystagmus, and astigmatism) in 67 patients with pathogenic mutations in the NAA10 cohort (54 inherited, 10 de novo; 65 missense, 2 frameshift) and 19 patients with pathogenic mutations in the NAA15 cohort (18 de novo; 8 frameshift, 4 missense, 4 nonsense, and 1 splice site). Patients were interviewed virtually or in-person to collect a comprehensive medical history verified by medical records. These records were then analyzed to calculate the prevalence of these ophthalmic manifestations in each cohort. Analysis revealed a higher prevalence of ophthalmic conditions in our NAA10 cohort compared to existing literature (myopia 25.4% vs. 4.7%; astigmatism 37.3% vs. 13.2%; strabismus 28.4% vs. 3.8%; CVI 22.4% vs. 8.5%, respectively). No statistically significant differences were identified between the NAA10 and NAA15 mutations. Our study includes novel neuroimaging of 13 NAA10 and 5 NAA15 probands, which provides no clear correlation between globe size and severity of comorbid ophthalmic disease. Finally, anecdotal evidence was compiled to underscore the importance of early ophthalmologic evaluations and therapeutic interventions.
... The phenotypes of the patients with pathogenic variants in NAA10 differ from severe phenotypes in males with p. Ser37Pro mutation (described as the Ogden syndrome) to the milder phenotypes found in both males and females, called NAA10-related syndrome [2,7,8,9]. Esmailpour et al. [10] reported a family with a mutation in the intron 7 splice donor site (c.471+2T>A) of NAA10 and Lenz microphthalmia syndrome. The first patients presented in the literature -deceased boys with Ogden syndrome -had many health problems, including a senile-like appearance, global developmental delay, hypotonia, structural heart defects, cardiomegaly and cardiac arrhythmias. ...
... Previously, splice variants in ALDH1A3, NAA10, RAX, TENM3, and VSX2 are already described to be associated with syndromic or non-syndromic A/M, but these were present either in exons or intron-exon junctions [28,[43][44][45][46]. To the best of our knowledge, this is the first study reporting the association of a deep intronic splice variant with A/M, and the first splice-altering variant identified in PXDN. ...
Anophthalmia and microphthalmia (A/M) are among the most severe congenital developmental eye disorders. Despite the advancements in genome screening technologies, more than half of A/M patients do not receive a molecular diagnosis. We included seven consanguineous families affected with A/M from Pakistani cohort and an unknown molecular basis. Single gene testing of FOXE3 was performed, followed by genome sequencing for unsolved probands in order to establish a genetic diagnosis for these families. All seven families were provided with a genetic diagnosis. The identified variants were all homozygous, classified as (likely) pathogenic and present in an A/M-associated gene. Targeted FOXE3 sequencing revealed two previously reported pathogenic FOXE3 variants in four families. In the remaining families, genome sequencing revealed a known pathogenic PXDN variant, a novel 13bp deletion in VSX2, and one novel deep intronic splice variant in PXDN. An in vitro splice assay was performed for the PXDN splice variant which revealed a severe splicing defect. Our study confirmed the utility of genome sequencing as a diagnostic tool for A/M-affected individuals. Furthermore, the identification of a novel deep intronic pathogenic variant in PXDN highlights the role of non-coding variants in A/M-disorders and the value of genome sequencing for the identification of this type of variants.
... Furthermore, the levels of remaining enzymatic activity and the diverse function of NAA10 were discussed as the foundation underlying the NAA10-associated phenotypes (19)(20)(21). Nevertheless, a solid conclusion could not be drawn yet due to the less affected individuals. ...
The NAA10 gene encodes the catalytic subunit of the N-terminal acetyltransferase protein complex A (NatA), which is supposed to acetylate approximately 40% of the human proteins. After the advent of next-generation sequencing, more variants in the NAA10 gene and Ogden syndrome (OMIM# 300855) have been reported. Individuals with NAA10 -related syndrome have a wide spectrum of clinical manifestations and the genotype–phenotype correlation is still far from being confirmed. Here, we report a three years old Chinese girl carrying a heterozygous de novo NAA10 [NM_003491: c. 247C > T, p. (Arg83Cys)] variant (dbSNP# rs387906701) (ClinVar# 208664) (OMIM# 300013.0010). The proband not only has some mild and common clinical manifestations, including dysmorphic features, developmental delay, obstructive hypertrophic cardiomyopathy, and arrhythmia, but also shows some rare clinical features such as exophthalmos, blue sclera, cutaneous capillary malformations, and adenoid hypertrophy. Our attempt is to expand the clinical phenotype associated with NAA10 -related syndrome and explore genotype–phenotype correlation with such syndrome.
... Although some papers have also suggested that there might be different allelic presentations or mechanisms of action for different variants involving NAA10, such as with microphthalmia present in males with splice-site [46] or frameshift [21] variants, the present study demonstrates that this is much more likely to be a phenotypic spectrum of one unitary disease. Although some do refer to this entire disease entity as Ogden syndrome, another name could be NAA10-related neurodevelopmental syndrome. ...
Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting 80% of cytosolic proteins in humans. The human essential gene, NAA10 , encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex, also including the accessory protein, NAA15. The full spectrum of human genetic variation in this pathway is currently unknown. Here we reveal the genetic landscape of variation in NAA10 and NAA15 in humans. Through a genotype-first approach, one clinician interviewed the parents of 56 individuals with NAA10 variants and 19 individuals with NAA15 variants, which were added to all known cases ( N = 106 for NAA10 and N = 66 for NAA15 ). Although there is clinical overlap between the two syndromes, functional assessment demonstrates that the overall level of functioning for the probands with NAA10 variants is significantly lower than the probands with NAA15 variants. The phenotypic spectrum includes variable levels of intellectual disability, delayed milestones, autism spectrum disorder, craniofacial dysmorphology, cardiac anomalies, seizures, and visual abnormalities (including cortical visual impairment and microphthalmia). One female with the p.Arg83Cys variant and one female with an NAA15 frameshift variant both have microphthalmia. The frameshift variants located toward the C-terminal end of NAA10 have much less impact on overall functioning, whereas the females with the p.Arg83Cys missense in NAA10 have substantial impairment. The overall data are consistent with a phenotypic spectrum for these alleles, involving multiple organ systems, thus revealing the widespread effect of alterations of the NTA pathway in humans.
... Human NATs are also involved in acute diseases. Numerous NAT subunits are upregulated in different forms of cancers [79] and, as described for point mutations in NAA10 gene, can be involved in the aetiology of intellectual disabilities and rare genetic diseases [80][81][82]. NATs act as both oncoproteins and tumour suppressors in human cancers. Alterations in NATs expression in vitro lead to cell cycle arrest, autophagy or apoptosis activation, highlighting that NATs target dozens of cellular processes. ...
Chromatin structural organization, gene expression and proteostasis are intricately regulated in a wide range of biological processes, both physiological and pathological. Protein acetylation, a major post-translational modification, is tightly involved in interconnected biological networks, modulating the activation of gene transcription and protein action in cells. A very large number of studies describe the pivotal role of the so-called acetylome (accounting for more than 80% of the human proteome) in orchestrating different pathways in response to stimuli and triggering severe diseases, including cancer. NAA60/NatF (N-terminal acetyltransferase F), also named HAT4 (histone acetyltransferase type B protein 4), is a newly discovered acetyltransferase in humans modifying N-termini of transmembrane proteins starting with M–K/M-A/M-V/M-M residues and is also thought to modify lysine residues of histone H4. Because of its enzymatic features and unusual cell localization on the Golgi membrane, NAA60 is an intriguing acetyltransferase that warrants biochemical and clinical investigation. Although it is still poorly studied, this review summarizes current findings concerning the structural hallmarks and biological role of this novel targetable epigenetic enzyme.
... ;https://doi.org/10.1101https://doi.org/10. /2022 variants either in NAA10 in both males and females (Bader et al. 2020;Casey et al. 2015;Cheng et al. 2019;McTiernan et al. 2021;Popp et al. 2015;Ree et al. 2019;Støve et al. 2018;Afrin et al. 2020;Esmailpour et al. 2014;Johnston et al. 2019;Gupta et al. 2019;Saunier et al. 2016;Maini et al. 2021) or in the heterodimeric protein partner encoded by NAA15 Cheng et al. 2018;Ritter et al. 2021;Ward et al. 2021;Tian et al. 2022). The collection of presenting symptoms for families with NAA10 variants is currently referred to as, "Ogden syndrome" or "NAA10-related syndrome", and "NAA15-related syndrome" for families with NAA15 variants. ...
... Additionally, some clinicians have also diagnosed females as having Ogden syndrome (Sidhu et al. 2017). Although some papers have also suggested that there might be different allelic presentations for different variants involving NAA10, such as with microphthalmia present in males with splice-site (Esmailpour et al. 2014) or frameshift variants, the present study demonstrates that this is much more likely to be a phenotypic spectrum of one unitary disease. ...
... ; https://doi.org/10.1101/2022.08.22.22279061 doi: medRxiv preprint published cases Esmailpour et al. 2014;Johnston et al. 2019). The cognitive functioning of the females with p.Arg83Cys missense in NAA10 is also similarly impaired as the other females with different missense changes (Figure 3), and there is a phenotypic spectrum including multiple organ systems in all of these females with missense changes in NAA10. ...
Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting 80% of cytosolic proteins in humans. The human essential gene, NAA10, encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex, also including the accessory protein, NAA15. The full spectrum of human genetic variation in this pathway is currently unknown. Here we reveal the genetic landscape of variation in NAA10 and NAA15 in humans. Through a genotype-first approach, one clinician interviewed the parents of 56 individuals with NAA10 variants and 19 individuals with NAA15 variants, which were added to all known cases (N=106 for NAA10 and N=66 for NAA15). Although there is clinical overlap between the two syndromes, functional assessment demonstrates that the overall level of functioning for the probands with NAA10 variants is significantly lower than the probands with NAA15 variants. The phenotypic spectrum includes variable levels of intellectual disability, delayed milestones, autism spectrum disorder, craniofacial dysmorphology, cardiac anomalies, seizures, and visual abnormalities (including cortical visual impairment and microphthalmia). One female with the p.Arg83Cys variant and one female with an NAA15 frameshift variant both have microphthalmia. The frameshift variants located toward the C-terminal end of NAA10 have much less impact on overall functioning, whereas the females with the p.Arg83Cys missense in NAA10 have substantial impairment. The overall data are consistent with a phenotypic spectrum for these alleles, involving multiple organ systems, thus revealing the widespread effect of alterations of the NTA pathway in humans.
... Visual impairments, such as central or cortical visual impairment, astigmatism or strabismus, appear to be a frequent phenotype occurring in half of all individuals with NAA10 missense variants (Supplementary Table S1). However, only polyadenylation signal (PAS) variants, splice and frameshift variants in NAA10 have been found to cause microphthalmia (Cheng et al. 2019;Esmailpour et al. 2014;Johnston et al. 2019). ...
... The majority of these variants have been biochemically characterised through enzymatic activity and/or stability assays Casey et al. 2015;Popp et al. 2015;Saunier et al. 2016;McTiernan et al. 2018McTiernan et al. , 2020McTiernan et al. , 2021Støve et al. 2018;Cheng et al. 2019;Ree et al. 2019;Bader et al. 2020;Afrin et al. 2020). Furthermore, a frameshift variant, a splice-site variant and three PAS variants in NAA10 have been associated with syndromic microphthalmia in 20 males (Cheng et al. 2019;Esmailpour et al. 2014;Johnston et al. 2019). A full overview of all NAA10 variants reported can be found in Supplementary Table S1. ...
NAA10 is the catalytic subunit of the N-terminal acetyltransferase complex, NatA, which is responsible for N-terminal acetylation of nearly half the human proteome. Since 2011, at least 21 different NAA10 missense variants have been reported as pathogenic in humans. The clinical features associated with this X-linked condition vary, but commonly described features include developmental delay, intellectual disability, cardiac anomalies, brain abnormalities, facial dysmorphism and/or visual impairment. Here, we present eight individuals from five families with five different de novo or inherited NAA10 variants. In order to determine their pathogenicity, we have performed biochemical characterisation of the four novel variants c.16G>C p.(A6P), c.235C>T p.(R79C), c.386A>C p.(Q129P) and c.469G>A p.(E157K). Additionally, we clinically describe one new case with a previously identified pathogenic variant, c.384T>G p.(F128L). Our study provides important insight into how different NAA10 missense variants impact distinct biochemical functions of NAA10 involving the ability of NAA10 to perform N-terminal acetylation. These investigations may partially explain the phenotypic variability in affected individuals and emphasise the complexity of the cellular pathways downstream of NAA10.
