Abstract
Congenital diaphragmatic hernia and other congenital diaphragmatic defects are associated with significant mortality and morbidity in neonates; however, the molecular basis of these developmental anomalies is unknown. In an analysis of E18.5 embryos derived from mice treated with N-ethyl-N-nitrosourea, we identified a mutation that causes pulmonary hypoplasia and abnormal diaphragmatic development. Fog2 (Zfpm2) maps within the recombinant interval carrying the N-ethyl-N-nitrosourea-induced mutation, and DNA sequencing of Fog2 identified a mutation in a splice donor site that generates an abnormal transcript encoding a truncated protein. Human autopsy cases with diaphragmatic defect and pulmonary hypoplasia were evaluated for mutations in FOG2. Sequence analysis revealed a de novo mutation resulting in a premature stop codon in a child who died on the first day of life secondary to severe bilateral pulmonary hypoplasia and an abnormally muscularized diaphragm. Using a phenotype-driven approach, we have established that Fog2 is required for normal diaphragm and lung development, a role that has not been previously appreciated. FOG2 is the first gene implicated in the pathogenesis of nonsyndromic human congenital diaphragmatic defects, and its necessity for pulmonary development validates the hypothesis that neonates with congenital diaphragmatic hernia may also have primary pulmonary developmental abnormalities.
Highlights
Congenital diaphragmatic defects are a spectrum of relatively common birth defects
Advances in the medical management of pulmonary hypoplasia may have decreased the mortality associated with congenital diaphragmatic hernia (CDH) patients who survive to receive care at high-volume centers [2,3], the populationbased mortality has been reported to be as great as 62%, and there are a large number of deaths prior to birth or to transfer to a tertiary care facility [4]
Positional cloning analysis identified Fog2 (Zfpm2) as a likely candidate, and DNA sequencing revealed a mutation in a splice donor site that generates an abnormal transcript encoding a truncated protein. This result suggested that we examine the orthologous gene in humans with similar developmental defects, and we report the finding of a de novo nonsense mutation in FOG2 in a patient who died at birth with a diaphragmatic defect and severe pulmonary hypoplasia
Summary
Congenital diaphragmatic defects are a spectrum of relatively common birth defects. The Bochdalek or posterolateral hernias (often referred to as congenital diaphragmatic hernia [CDH]) occur in 1/3,000 live births [1], and these are the most common type of diaphragmatic defect presenting at birth, diaphragmatic aplasia and diaphragmatic muscularization defects (eventrations) may have a similar clinical presentation.Making specific anatomic distinctions among these types of defects can be difficult without direct gross (intraoperative or postmortem) examination. Advances in the medical management of pulmonary hypoplasia may have decreased the mortality associated with CDH patients who survive to receive care at high-volume centers [2,3], the populationbased mortality has been reported to be as great as 62%, and there are a large number of deaths prior to birth or to transfer to a tertiary care facility [4]. As these patients commonly present with severe respiratory failure at birth, therapy has been centered around developing better methods to provide ventilatory support while not producing further lung injury. The morbidity in those who survive is high, and many patients survive with chronic respiratory insufficiency, cognitive and neuromotor deficits, and hearing loss as a result of necessary intensive interventions and associated structural and irreversible developmental abnormalities [8,9,10,11]
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