The Genetics of Primary Microcephaly Jayaraman, Divya; Bae, Byoung-Il; Walsh, Christopher A
Annual review of genomics and human genetics,
08/2018, Letnik:
19, Številka:
1
Journal Article
Recenzirano
Primary microcephaly (MCPH, for "microcephaly primary hereditary") is a disorder of brain development that results in a head circumference more than 3 standard deviations below the mean for age and ...gender. It has a wide variety of causes, including toxic exposures, in utero infections, and metabolic conditions. While the genetic microcephaly syndromes are relatively rare, studying these syndromes can reveal molecular mechanisms that are critical in the regulation of neural progenitor cells, brain size, and human brain evolution. Many of the causative genes for MCPH encode centrosomal proteins involved in centriole biogenesis. However, other MCPH genes fall under different mechanistic categories, notably DNA replication and repair. Recent gene discoveries and functional studies have implicated novel cellular processes, such as cytokinesis, centromere and kinetochore function, transmembrane or intracellular transport, Wnt signaling, and autophagy, as well as the apical polarity complex. Thus, MCPH genes implicate a wide variety of molecular and cellular mechanisms in the regulation of cerebral cortical size during development.
Mutations in several genes encoding centrosomal proteins dramatically decrease the size of the human brain. We show that Aspm (abnormal spindle-like, microcephaly-associated) and Wdr62 (WD ...repeat-containing protein 62) interact genetically to control brain size, with mice lacking Wdr62, Aspm, or both showing gene dose-related centriole duplication defects that parallel the severity of the microcephaly and increased ectopic basal progenitors, suggesting premature delamination from the ventricular zone. Wdr62 and Aspm localize to the proximal end of the mother centriole and interact physically, with Wdr62 required for Aspm localization, and both proteins, as well as microcephaly protein Cep63, required to localize CENPJ/CPAP/Sas-4, a final common target. Unexpectedly, Aspm and Wdr62 are required for normal apical complex localization and apical epithelial structure, providing a plausible unifying mechanism for the premature delamination and precocious differentiation of progenitors. Together, our results reveal links among centrioles, apical proteins, and cell fate, and illuminate how alterations in these interactions can dynamically regulate brain size.
•Wdr62 and Aspm interact genetically to control brain size in mice•Loss of Wdr62 or Aspm causes centriole duplication defects proportional to microcephaly•WDR62 and ASPM are maternal centriolar proteins that recruit CPAP to the centrosome•Loss of Wdr62 and Aspm causes gene dose-dependent disruption of the apical complex
Jayaraman et al. show that microcephaly proteins Wdr62 and Aspm localize to the maternal centriole and physically interact. Mice lacking Wdr62, Aspm, or both show gene dose-dependent defects in brain size, centriole duplication, centrosomal localization of CPAP, and the apical complex, which plays a critical role in cell fate.
Introduction: Chronic kidney disease (CKD) affects every organ system including the eye. Aim: To conduct a thorough ocular examination in the patients of CKD and to analyse the findings. Materials ...and Methods: A total of 100 cases were collected from the nephrology unit of our tertiary centre. This was a cross-sectional, hospital-based study. Results: The commonest causes for visual impairment were maculopathy followed by cataracts. The other ocular findings were progressive pterygium, keratitis, central retinal vein occlusion (CRVO), retinal detachments (RDs), vitreous haemorrhage (VH) and disc-related changes. Hypertensive retinopathy (HR) was more prevalent and tended to be more severe as the renal disease progressed. More severe grades of diabetic retinopathy (DR) were detected with increasing severity of the renal disease. Conclusion: This study shows the importance of ocular evaluation of patients with CKD.
Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in ...which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome. Thus, centriolar satellites build a MCPH complex critical for human neurodevelopment that promotes CDK2 centrosomal localization and centriole duplication.
While next-generation sequencing has accelerated the discovery of human disease genes, progress has been largely limited to the "low hanging fruit" of mutations with obvious exonic coding or ...canonical splice site impact. In contrast, the lack of high-throughput, unbiased approaches for functional assessment of most noncoding variants has bottlenecked gene discovery. We report the integration of transcriptome sequencing (RNA-seq), which surveys all mRNAs to reveal functional impacts of variants at the transcription level, into the gene discovery framework for a unique human disease, microcephaly-micromelia syndrome (MMS). MMS is an autosomal recessive condition described thus far in only a single First Nations population and causes intrauterine growth restriction, severe microcephaly, craniofacial anomalies, skeletal dysplasia, and neonatal lethality. Linkage analysis of affected families, including a very large pedigree, identified a single locus on Chromosome 21 linked to the disease (LOD > 9). Comprehensive genome sequencing did not reveal any pathogenic coding or canonical splicing mutations within the linkage region but identified several nonconserved noncoding variants. RNA-seq analysis detected aberrant splicing in
due to one of these noncoding variants, showing a causative role for
disruption in MMS. We show that
is expressed in progenitor cells of embryonic human brain and other proliferating tissues, is co-expressed with components of the DNA replication machinery, and that
is essential for early embryonic development in mice as well, suggesting an essential conserved role for DONSON in the cell cycle. Our results demonstrate the utility of integrating transcriptomics into the study of human genetic disease when DNA sequencing alone is not sufficient to reveal the underlying pathogenic mutation.
Methods A retrospective chart review was performed on pediatric return visit patients (ages 4-20) seen in the allergy/immunology clinic at Children's Hospital of Pittsburgh from January 2012-June ...2014 with the diagnosis of asthma based on ICD-9 coding.
Genetic Changes Shaping the Human Brain Bae, Byoung-Il; Jayaraman, Divya; Walsh, Christopher A.
Developmental cell,
02/2015, Letnik:
32, Številka:
4
Journal Article
Recenzirano
Odprti dostop
The development and function of our brain are governed by a genetic blueprint, which reflects dynamic changes over the history of evolution. Recent progress in genetics and genomics, facilitated by ...next-generation sequencing and single-cell sorting, has identified numerous genomic loci that are associated with a neuroanatomical or neurobehavioral phenotype. Here, we review some of the genetic changes in both protein-coding and noncoding regions that affect brain development and evolution, as well as recent progress in brain transcriptomics. Understanding these genetic changes may provide novel insights into neurological and neuropsychiatric disorders, such as autism and schizophrenia.
We identified in an adult with ectodermal dysplasia and immunodeficiency a germline, gain-of-function mutation, K171R, in IKBKB. The K171R mouse immunologic phenotype parallels human, suggesting ...IKBKB K171R underlies a novel immunodeficiency syndrome.
PDF
