Infantile hemangiomas and retinopathy of prematurity: clues to the regulation of vasculogenesis.

UNLABELLED: Retinopathy of prematurity (ROP) and infantile hemangiomas are vascular disorders that may share common mechanisms. This study examined a potential clinical association between these disorders in populations of preterm infants at two hospitals in the USA and Hungary. Clinically collected data from infants with gestational ages less than 32 weeks born between May 1, 2007 and December 31, 2010 seen in the University of Iowa Children's Hospital or the Department of Obstetrics and Gynecology, University of Pécs, were abstracted from electronic medical records and entered into a study database. Demographic and clinical variables were examined as potential covariates to the disorders of interest. Data were initially analyzed by center and then combined through meta-analysis. Six hundred eighty-four subjects were studied: 236 from Pécs and 448 from Iowa. There were no significant demographic differences between populations. Univariate analysis on each study population yielded covariates to ROP in each population, including infantile hemangioma, which were entered into a logistic regression model. These models were combined through random-effects meta-analysis and demonstrated a significant relationship between infantile hemangioma and ROP (odds ratio = 1.84, 95 % confidence interval 1.08-3.12). CONCLUSION: Infantile hemangioma and ROP co-occur in premature infant populations. Further studies are needed to investigate the pathogenesis of both disorders.

The effect of Dnaaf5 gene dosage on primary ciliary dyskinesia phenotypes.

DNAAF5 is a dynein motor assembly factor associated with the autosomal heterogenic recessive condition of motile cilia, primary ciliary dyskinesia (PCD). The effects of allele heterozygosity on motile cilia function are unknown. We used CRISPR-Cas9 genome editing in mice to recreate a human missense variant identified in patients with mild PCD and a second, frameshift null deletion in Dnaaf5 . Litters with Dnaaf5 heteroallelic variants showed distinct missense and null gene dosage effects. Homozygosity for the null Dnaaf5 alleles was embryonic lethal. Compound heterozygous animals with the missense and null alleles showed severe disease manifesting as hydrocephalus and early lethality. However, animals homozygous for the missense mutation had improved survival, with partial preserved cilia function and motor assembly observed by ultrastructure analysis. Notably, the same variant alleles exhibited divergent cilia function across different multiciliated tissues. Proteomic analysis of isolated airway cilia from mutant mice revealed reduction in some axonemal regulatory and structural proteins not previously reported in DNAAF5 variants. While transcriptional analysis of mouse and human mutant cells showed increased expression of genes coding for axonemal proteins. Together, these findings suggest allele-specific and tissue-specific molecular requirements for cilia motor assembly that may affect disease phenotypes and clinical trajectory in motile ciliopathies. Brief Summary: A mouse model of human DNAAF5 primary ciliary dyskinesia variants reveals gene dosage effects of mutant alleles and tissue-specific molecular requirements for cilia motor assembly.

The effect of Dnaaf5 gene dosage on primary ciliary dyskinesia phenotypes.

DNAAF5 is a dynein motor assembly factor associated with the autosomal heterogenic recessive condition of motile cilia, primary ciliary dyskinesia (PCD). The effects of allele heterozygosity on motile cilia function are unknown. We used CRISPR-Cas9 genome editing in mice to recreate a human missense variant identified in patients with mild PCD and a second, frameshift-null deletion in Dnaaf5. Litters with Dnaaf5 heteroallelic variants showed distinct missense and null gene dosage effects. Homozygosity for the null Dnaaf5 alleles was embryonic lethal. Compound heterozygous animals with the missense and null alleles showed severe disease manifesting as hydrocephalus and early lethality. However, animals homozygous for the missense mutation had improved survival, with partially preserved cilia function and motor assembly observed by ultrastructure analysis. Notably, the same variant alleles exhibited divergent cilia function across different multiciliated tissues. Proteomic analysis of isolated airway cilia from mutant mice revealed reduction in some axonemal regulatory and structural proteins not previously reported in DNAAF5 variants. Transcriptional analysis of mouse and human mutant cells showed increased expression of genes coding for axonemal proteins. These findings suggest allele-specific and tissue-specific molecular requirements for cilia motor assembly that may affect disease phenotypes and clinical trajectory in motile ciliopathies.

Impact of Motile Ciliopathies on Human Development and Clinical Consequences in the Newborn.

Motile cilia are hairlike organelles that project outward from a tissue-restricted subset of cells to direct fluid flow. During human development motile cilia guide determination of the left-right axis in the embryo, and in the fetal and neonatal periods they have essential roles in airway clearance in the respiratory tract and regulating cerebral spinal fluid flow in the brain. Dysregulation of motile cilia is best understood through the lens of the genetic disorder primary ciliary dyskinesia (PCD). PCD encompasses all genetic motile ciliopathies resulting from over 60 known genetic mutations and has a unique but often underrecognized neonatal presentation. Neonatal respiratory distress is now known to occur in the majority of patients with PCD, laterality defects are common, and very rarely brain ventricle enlargement occurs. The developmental function of motile cilia and the effect and pathophysiology of motile ciliopathies are incompletely understood in humans. In this review, we will examine the current understanding of the role of motile cilia in human development and clinical considerations when assessing the newborn for suspected motile ciliopathies.