September 1, 2000Journal of Neurology Neurosurgery & Psychiatry247 citationsOpen Access
NEUROLOGICAL ASPECTS OF TROPICAL DISEASE: Tetanus
Key Result
Three PLD1 gene mutations were identified in patients with severe congenital valve malformations, and PLD1 knockout mice exhibited marked tricuspid regurgitation and pulmonic valve defects.
Study Design
Type
Observational (n=5)
Structured PICO
P
Population
5 patients with severe valvular malformations involving the pulmonic, tricuspid and mitral valves from two unrelated families, along with yeast, chick embryo, and PLD1 knockout mice models.
I
Intervention
Whole-exome sequencing and functional assessment of PLD1 mutations
O
Outcome
Identification of genetic mutations and functional/phenotypic assessment in animal modelssurrogate
Mutations in the PLD1 gene are associated with severe congenital valve malformations, supporting its role in normal heart valvulogenesis.
Abstract
Background The underlying molecular aetiology of congenital heart defects is largely unknown. The aim of this study was to explore the genetic basis of non-syndromic severe congenital valve malformations in two unrelated families. Methods Whole-exome analysis was used to identify the mutations in five patients who suffered from severe valvular malformations involving the pulmonic, tricuspid and mitral valves. The significance of the findings was assessed by studying sporulation of yeast carrying a homologous Phospholipase D (PLD1) mutation, in situ hybridisation in chick embryo and echocardiography and histological examination of hearts of PLD1 knockout mice. Results Three mutations, p.His442Pro, p.Thr495fs32* and c.2882+2T>C, were identified in the PLD1 gene. The mutations affected highly conserved sites in the PLD1 protein and the p.His442Pro mutation produced a strong loss of function phenotype in yeast homologous mutant strain. Here we show that in chick embryos PLD1 expression is confined to the forming heart (E2–E8) and homogeneously expressed all over the heart during days E2–E3. Thereafter its expression decreases, remaining only adjacent to the atrioventricular valves and the right ventricular outflow tract. This pattern of expression follows the known dynamic patterning of apoptosis in the developing heart, consistent with the known role of PLD1 in the promotion of apoptosis. In hearts of PLD1 knockout mice, we detected marked tricuspid regurgitation, right atrial enlargement, and increased flow velocity, narrowing and thickened leaflets of the pulmonic valve. Conclusions The findings support a role for PLD1 in normal heart valvulogenesis.