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.
Autism is characterized by a broad spectrum of clinical manifestations including qualitative impairments in social interactions and communication, and repetitive and stereotyped patterns of behavior. ...Abnormal acceleration of brain growth in early childhood, signs of slower growth of neurons, and minicolumn developmental abnormalities suggest multiregional alterations. The aim of this study was to detect the patterns of focal qualitative developmental defects and to identify brain regions that are prone to developmental alterations in autism. Formalin-fixed brain hemispheres of 13 autistic (4–60 years of age) and 14 age-matched control subjects were embedded in celloidin and cut into 200-μm-thick coronal sections, which were stained with cresyl violet and used for neuropathological evaluation. Thickening of the subependymal cell layer in two brains and subependymal nodular dysplasia in one brain is indicative of active neurogenesis in two autistic children. Subcortical, periventricular, hippocampal and cerebellar heterotopias detected in the brains of four autistic subjects (31%) reflect abnormal neuronal migration. Multifocal cerebral dysplasia resulted in local distortion of the cytoarchitecture of the neocortex in four brains (31%), of the entorhinal cortex in two brains (15%), of the cornu Ammonis in four brains and of the dentate gyrus in two brains. Cerebellar flocculonodular dysplasia detected in six subjects (46%), focal dysplasia in the vermis in one case, and hypoplasia in one subject indicate local failure of cerebellar development in 62% of autistic subjects. Detection of flocculonodular dysplasia in only one control subject and of a broad spectrum of focal qualitative neuropathological developmental changes in 12 of 13 examined brains of autistic subjects (92%) reflects multiregional dysregulation of neurogenesis, neuronal migration and maturation in autism, which may contribute to the heterogeneity of the clinical phenotype.
The neuronal ceroid lipofuscinosis 2 (NCL2) or classic late-infantile neuronal ceroid lipofuscinosis (LINCL) is a neurogenetic disorder caused by mutations in the TPPI gene, which codes for the ...lysosomal tripeptidyl peptidase 1 (TPPI) EC 3.4.14.9. Loss of functional TPPI activity results in progressive visual and neurological symptoms starting at around 1-2 years of age causing early death.
We report a DBS-based TPPI assay that cleaves a synthetic tetrapeptide substrate generating a product that is detected by HPLC. Probands and carriers were identified with 100% accuracy (7 probands, 30 carriers, 13 controls).
The assay detected a single TPPI activity at a lower pH towards the substrate tested. TPPI activity measurable when extracted at lower pH while inactive at neutral pH showed steady increase for at least 8 h incubation. No loss in TPPI activity was observed when DBS were stored for at least 2 weeks either in freezer, refrigerator, room temperature or 42 °C.
A sequence variant causing Arg339Gln substitution in a proband had 12% TPPI. TPPI activity can be reliably measured in DBS, giving an opportunity to diagnose NCL2 at birth and refer patients for enzyme replacement or other therapies for earliest intervention, or alternatively offers a second-tier confirmatory test.
Telomere shortening was shown to parallel Alzheimer's disease (AD) associated dementia. By using a dual PNA Probe system we have developed a practical method for comparing telomere length in ...T‐lymphocyte interphases from individuals with Down syndrome (DS) with and without “mild cognitive impairment” (MCI‐DS) and demonstrated that telomere length can serve as a valid biomarker for the onset of MCI‐DS in this high‐risk population. To verify progressive cognitive decline we have now examined sequential changes in telomere length in 10 adults with DS (N = 4 Female, N = 6 Male) developing MCI‐DS. Cases were selected blind to telomere length from a sample of adults with DS previously enrolled in a prospective longitudinal study at 18‐month intervals with clinical and telomere assessments: (1) MCI‐DS group data were collected approximately three years prior to development of MCI‐DS; (2) 18 months later; (3) when MCI‐DS was first observed. These telomere measures were compared to those from another 10 adults with DS matched by sex and approximate age but without indications of MCI‐DS (Controls). PNA (peptide nucleic acid) probes for telomeres together with a chromosome two centromere probe were used. Findings indicated telomere shortening over time for both Cases and Controls. Group differences emerged by 18‐months prior to recognition of MCI‐DS onset and completely non‐overlapping distributions of telomere measures were observed by the time of MCI‐DS onset. This study adds to accumulating evidence of the value of telomere length, as an early biomarker of AD progression in adults with Down syndrome.
Amino-terminal acetylation is catalyzed by a set of N-terminal acetyltransferases (NATs). The NatA complex (including X-linked Naa10 and Naa15) is the major acetyltransferase, with 40–50% of all ...mammalian proteins being potential substrates. However, the overall role of amino-terminal acetylation on a whole-organism level is poorly understood, particularly in mammals. Male mice lacking
Naa10
show no globally apparent in vivo amino-terminal acetylation impairment and do not exhibit complete embryonic lethality. Rather
Naa10
nulls display increased neonatal lethality, and the majority of surviving undersized mutants exhibit a combination of hydrocephaly, cardiac defects, homeotic anterior transformation, piebaldism, and urogenital anomalies.
Naa12
is a previously unannotated
Naa10
-like paralog with NAT activity that genetically compensates for
Naa10
. Mice deficient for
Naa12
have no apparent phenotype, whereas mice deficient for
Naa10
and
Naa12
display embryonic lethality. The discovery of
Naa12
adds to the currently known machinery involved in amino-terminal acetylation in mice.
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. The current study involves a total of 58 distinct participants; of these, 43 caregivers were interviewed using the Vineland‐3 and answered a survey regarding therapy and other questions, 10 of whom completed the Vineland‐3 but did not answer the survey, and 5 participants who answered the survey but have not yet performed the Vineland‐3 due to language constraints. The average age at the time of the most recent assessment was 12.4 years, with individuals ranging in age from 11 months to 40.2 years. Using Vineland‐3 scores, we show decline in cognitive function over time in individuals with Ogden syndrome (n = 53). Sub‐domain analysis found the decline to be present across all modalities. In addition, 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. Additional investigation between seizure and non‐seizure groups showed no significant difference in adaptive behavior outcomes. A 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.
Our study of 61 children with NAA10‐related neurodevelopmental syndrome, an X‐linked disorder due to NAA10 gene variants, demonstrated a high prevalence of growth failure, with weight and height ...percentiles often in the failure‐to‐thrive diagnostic range; however, dramatic weight fluctuations and phenotypic variability is evidenced in the growth parameters of this population. Although never previously explored in depth, the gastrointestinal pathology associated with NAA10‐related neurodevelopmental syndrome includes feeding difficulties in infancy, dysphagia, GERD/silent reflux, vomiting, constipation, diarrhea, bowel incontinence, and presence of eosinophils on esophageal endoscopy, in order from most to least prevalent. Additionally, the gastrointestinal symptom profile for children with this syndrome has been expanded to include eosinophilic esophagitis, cyclic vomiting syndrome, Mallory Weiss tears, abdominal migraine, esophageal dilation, and subglottic stenosis. Although the exact cause of poor growth in NAA10‐related neurodevelopmental syndrome probands is unclear and the degree of contribution to this problem by GI symptomatology remains uncertain, an analysis including nine G‐tube or GJ‐tube fed probands demonstrates that G/GJ‐tubes are overall efficacious with respect to improvements in weight gain and caregiving. The choice to insert a gastrostomy or gastrojejunal tube to aid with weight gain is often a challenging decision to make for parents, who may alternatively choose to rely on oral feeding, caloric supplementation, calorie tracking, and feeding therapy. In this case, if NAA10‐related neurodevelopmental syndrome children are not tracking above the failure to thrive (FTT) range past 1 year of age despite such efforts, the treating physicians should be consulted regarding possibly undergoing G‐tube placement to avoid prolonged growth failure. If G‐tubes are not immediately inducing weight gain after insertion, recommendations could include altering formula, increasing caloric input, or exchanging a G‐tube for a GJ‐tube by means of a minimally invasive procedure.
Ankyrin Repeat Domain 11 (ANKRD11) gene mutations are associated with KBG syndrome, a developmental disability that affects multiple organ systems. The function of ANKRD11 in human growth and ...development is not clear, but gene knockout or mutation are lethal in mice embryos and/or pups. In addition, it plays a vital role in chromatin regulation and transcription. Individuals with KBG syndrome are often misdiagnosed or remain undiagnosed until later in life. This is largely due to KBG syndrome's varying and nonspecific phenotypes as well as a lack of accessible genetic testing and prenatal screening. This study documents perinatal outcomes for individuals with KBG syndrome. We obtained data from 42 individuals through videoconferences, medical records, and emails. 45.2% of our cohort was born by C‐section, 33.3% had a congenital heart defect, 23.8% were born prematurely, 23.8% were admitted to the NICU, 14.3% were small for gestational age, and 14.3% of the families had a history of miscarriage. These rates were higher in our cohort compared to the overall population, including non‐Hispanic and Hispanic populations. Other reports included feeding difficulties (21.4%), neonatal jaundice (14.3%), decreased fetal movement (7.1%), and pleural effusions in utero (4.7%). Comprehensive perinatal studies about KBG syndrome and updated documentation of its phenotypes are important in ensuring prompt diagnosis and can facilitate correct management.
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