Since 2011, eight males with an X-linked recessive disorder (Ogden syndrome, MIM #300855) associated with the same missense variant p.(Ser37Pro) in the NAA10 gene have been described. After the ...advent of whole exome sequencing, many NAA10 variants have been reported as causative of syndromic or non-syndromic intellectual disability in both males and females. The NAA10 gene lies in the Xq28 region and encodes the catalytic subunit of the major N-terminal acetyltransferase complex NatA, which acetylates almost half the human proteome. Here, we present a young female carrying a de novo NAA10 NM_003491:c.247C > T, p.(Arg83Cys) variant. The 18-year-old girl has severely delayed motor and language development, autistic traits, postnatal growth failure, facial dysmorphisms, interventricular septal defect, neuroimaging anomalies and epilepsy. Our attempt is to expand and compare genotype–phenotype correlation in females with NAA10-related syndrome. A detailed clinical description could have relevant consequences for the clinical management of known and newly identified individuals.
The heterogeneous family of complexes comprising Polycomb repressive complex 1 (PRC1) is instrumental for establishing facultative heterochromatin that is repressive to transcription. However, two ...PRC1 species, ncPRC1.3 and ncPRC1.5, are known to comprise novel components, AUTS2, P300, and CK2, that convert this repressive function to that of transcription activation. Here, we report that individuals harboring mutations in the HX repeat domain of AUTS2 exhibit defects in AUTS2 and P300 interaction as well as a developmental disorder reflective of Rubinstein-Taybi syndrome, which is mainly associated with a heterozygous pathogenic variant in CREBBP/EP300. Moreover, the absence of AUTS2 or mutation in its HX repeat domain gives rise to misregulation of a subset of developmental genes and curtails motor neuron differentiation of mouse embryonic stem cells. The transcription factor nuclear respiratory factor 1 (NRF1) has a novel and integral role in this neurodevelopmental process, being required for ncPRC1.3 recruitment to chromatin.
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•The AUTS2 HX repeat recruits P300 for ncPRC1.3-mediated transcription activation•Mutations in the HX repeat phenocopy CREBBP/EP300 mutations in RSTS•NRF1 recruits ncPRC1.3, which activates a subset of genes fostering neuronal development•Recruitment of P300 and ncPRC1.3 is required for neuronal progenitor differentiation
Liu et al. report that mutations in the HX repeat of AUTS2 derived from affected individuals disrupt its interaction with P300, thwarting AUTS2-ncPRC1.3-mediated active transcription. Such mutations reflect those in P300 proper with respect to RSTS. Moreover, NRF1-mediated AUTS2 recruitment is paramount for activation of AUTS2-ncPRC1.3 targets and brain development.
De novo variants are a leading cause of neurodevelopmental disorders (NDDs), but because every monogenic NDD is different and usually extremely rare, it remains a major challenge to understand the ...complete phenotype and genotype spectrum of any morbid gene. According to OMIM, heterozygous variants in KDM6B cause “neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities.” Here, by examining the molecular and clinical spectrum of 85 reported individuals with mostly de novo (likely) pathogenic KDM6B variants, we demonstrate that this description is inaccurate and potentially misleading. Cognitive deficits are seen consistently in all individuals, but the overall phenotype is highly variable. Notably, coarse facies and distal skeletal anomalies, as defined by OMIM, are rare in this expanded cohort while other features are unexpectedly common (e.g., hypotonia, psychosis, etc.). Using 3D protein structure analysis and an innovative dual Drosophila gain-of-function assay, we demonstrated a disruptive effect of 11 missense/in-frame indels located in or near the enzymatic JmJC or Zn-containing domain of KDM6B. Consistent with the role of KDM6B in human cognition, we demonstrated a role for the Drosophila KDM6B ortholog in memory and behavior. Taken together, we accurately define the broad clinical spectrum of the KDM6B-related NDD, introduce an innovative functional testing paradigm for the assessment of KDM6B variants, and demonstrate a conserved role for KDM6B in cognition and behavior. Our study demonstrates the critical importance of international collaboration, sharing of clinical data, and rigorous functional analysis of genetic variants to ensure correct disease diagnosis for rare disorders.
Clinical and molecular analysis of the KDM6B-related neurodevelopmental disorder highlights inaccuracies in its current OMIM definition and demonstrates the critical importance of international collaboration, sharing of clinical data, and rigorous functional analysis of genetic variants for an unbiased, accurate, and comprehensive definition of rare genetic disorders.
The catalytic subunit of human cytomegalovirus (HCMV) DNA polymerase pUL54 is a 1242‐amino‐acid protein, whose function, stimulated by the processivity factor, phosphoprotein UL44 (ppUL44), is ...essential for viral replication. The C‐terminal residues (amino acids 1220–1242) of pUL54 have been reported to be sufficient for ppUL44 binding in vitro. Although believed to be important for functioning in the nuclei of infected cells, no data are available on either the interaction of pUL54 with ppUL44 in living mammalian cells or the mechanism of pUL54 nuclear transport and its relationship with that of ppUL44. The present study examines for the first time the nuclear import pathway of pUL54 and its interaction with ppUL44 using dual color, quantitative confocal laser scanning microscopy on live transfected cells and quantitative gel mobility shift assays. We showed that of two nuclear localization signals (NLSs) located at amino acids 1153–1159 (NLSA) and 1222–1227 (NLSB), NLSA is sufficient to confer nuclear localization on green fluorescent protein (GFP) by mediating interaction with importin α/β. We also showed that pUL54 residues 1213–1242 are sufficient to confer ppUL44 binding abilities on GFP and that pUL54 and ppUL44 can be transported to the nucleus as a complex. Our work thus identified distinct sites within the HCMV DNA polymerase, which represent potential therapeutic targets and establishes the molecular basis of UL54 nuclear import.
KBG syndrome is caused by haploinsufficiency of
and is characterised by macrodontia of upper central incisors, distinctive facial features, short stature, skeletal anomalies, developmental delay, ...brain malformations and seizures. The central nervous system (CNS) and skeletal features remain poorly defined.
CNS and/or skeletal imaging were collected from molecularly confirmed individuals with KBG syndrome through an international network. We evaluated the original imaging and compared our results with data in the literature.
We identified 53 individuals, 44 with CNS and 40 with skeletal imaging. Common CNS findings included incomplete hippocampal inversion and posterior fossa malformations; these were significantly more common than previously reported (63.4% and 65.9% vs 1.1% and 24.7%, respectively). Additional features included patulous internal auditory canal, never described before in KBG syndrome, and the recurrence of ventriculomegaly, encephalic cysts, empty sella and low-lying conus medullaris. We found no correlation between these structural anomalies and epilepsy or intellectual disability. Prevalent skeletal findings comprised abnormalities of the spine including scoliosis, coccygeal anomalies and cervical ribs. Hand X-rays revealed frequent abnormalities of carpal bone morphology and maturation, including a greater delay in ossification compared with metacarpal/phalanx bones.
This cohort enabled us to describe the prevalence of very heterogeneous neuroradiological and skeletal anomalies in KBG syndrome. Knowledge of the spectrum of such anomalies will aid diagnostic accuracy, improve patient care and provide a reference for future research on the effects of
variants in skeletal and brain development.
Osteocraniostenosis (OCS, OMIM #602361) is a severe, usually lethal condition characterized by gracile bones with thin diaphyses, a cloverleaf-shaped skull and splenic hypo/aplasia. The condition is ...caused by heterozygous mutations in the
gene and is allelic to the non-lethal, dominant disorder Kenny-Caffey syndrome (KCS, OMIM #127000). Here we report two new cases of OCS, including one with a detailed pathological examination. We review the main diagnostic signs of OCS both before and after birth based on our observations and on the literature. We then review the current knowledge on the mutational spectrum of
associated with either OCS or KCS, including three novel variants, both from one of the OCS fetuses described here, and from further cases diagnosed at our centers. This report refines the previous knowledge on OCS and expands the mutational spectrum that results in either OCS or KCS.
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