Mitral valve prolapse (MVP) affects 1 in 40 people and is the most common indication for mitral valve surgery. MVP can cause arrhythmias, heart failure, and sudden cardiac death, and to date, the causes of this disease are poorly understood. We now demonstrate that defects in primary cilia genes and their regulated pathways can cause MVP in familial and sporadic nonsyndromic MVP cases. Our expression studies and genetic ablation experiments confirmed a role for primary cilia in regulating ECM deposition during cardiac development. Loss of primary cilia during development resulted in progressive myxomatous degeneration and profound mitral valve pathology in the adult setting. Analysis of a large family with inherited, autosomal dominant nonsyndromic MVP identified a deleterious missense mutation in a cilia gene, DZIP1. A mouse model harboring this variant confirmed the pathogenicity of this mutation and revealed impaired ciliogenesis during development, which progressed to adult myxomatous valve disease and functional MVP. Relevance of primary cilia in common forms of MVP was tested using pathway enrichment in a large population of patients with MVP and controls from previously generated genome-wide association studies (GWAS), which confirmed the involvement of primary cilia genes in MVP. Together, our studies establish a developmental basis for MVP through altered cilia-dependent regulation of ECM and suggest that defects in primary cilia genes can be causative to disease phenotype in some patients with MVP.

Background Bicuspid aortic valve (BAV) disease is the most common congenital heart defect affecting 0.5–1.2% of the population and causes significant morbidity and mortality. Only a few genes have been identified in pedigrees and no single gene-model explains BAV inheritance, thus supporting a complex genetic network of interacting genes. However, patients with rare syndromic diseases that stem from alterations in the structure and function of primary cilia (“ciliopathies”) exhibit BAV as a frequent cardiovascular finding, suggesting primary cilia may factor broadly in disease etiology. Results Our data are the first to demonstrate that primary cilia are expressed on aortic valve mesenchymal cells during embryonic development and are lost as these cells differentiate into collagen-secreting fibroblastic-like cells. The function of primary cilia was tested by genetically ablating the critical ciliogenic gene, Ift88. Loss of Ift88 resulted in abrogation of primary cilia and increased fibrogenic ECM production. Consequentially, stratification of ECM boundaries normally present in the aortic valve were lost and a highly penetrant BAV phenotype was evident at birth. Conclusions Our data support cilia as a novel cellular mechanism for restraining ECM production during aortic valve development and broadly implicate these structures in the etiology of BAV disease in humans.

—High circulating levels of phenylalanine caused depletions of threonine, valine, methionine, isoleucine, leucine, histidine, tryptophan, and tyrosine in immature and adult rat brains. The branched‐chain amino acids were most affected. Their reductions ranged between 38–64 per cent of control values when phenylalanine was administered either parenterally or in the diet. The pattern of cerebral amino acid depletions found in phenylalanine‐injected infant rats was similar to that of the adults. Phenylalanine loading caused depletions in serum amino acid levels in adult rats, but in infant rats the serum levels were either unchanged or somewhat elevated. Tyrosine, when administered to adult rats either parenterally or via the diet, caused cerebral depletions in essential amino acids, but the depletions were not as striking as with phenylalanine. In both the infant and adult rat, brain‐blood ratios of most of the essential amino acids were significantly reduced by phenylalanine loading.

—The characteristics of the accumulation of 14 L‐amino acids (Leu, Ileu, Val, His, Tyr, Phe, Gly, Ala, Ser, Thr, Asp, Pro, Arg and Lys) by synaptosomal fractions prepared from rat brains were studied. Distinct differences were observed in the ion requirements for the accumulation of these amino acids. The accumulation of Asp and Pro alone showed a total requirement for Na+; uptakes of the other amino acids were either maximal in Na+‐free media or only partially dependent on the presence of external Na+. With brain maturation, two types of developmental alterations could be distinguished: (1) changes in rates of influx, and (2) changes in the effects of ions. Synaptosomal fractions prepared from brains of immature rats accumulated Leu, Arg and Lys to a greater extent and Val, Tyr, Pro and Asp to a lesser extent than did the fractions prepared from brains of mature animals. The accumulation of Ser and Thr by immature fractions was partially dependent on external Na+, whereas their accumulation by adult fractions was Na+‐independent. These alterations in Na+ requirements coincided with developmental changes in mutual inhibitions of amino acid transport.

The Na+-dependent synaptosomal uptakes of proline, aspartic acid, glutamic acid, and gamma-aminobutyric acid were strong inhibited by monounsaturated fatty acids. With oleic acid, half-maximal inhibition was observed at about 15 microM. The Na+-independent uptakes of leucine, phenylalanine, histidine, and valine were less sensitive to inhibition by the unsaturated fatty acids. In contrast, the uptakes of all of these amino acids were unaffected by saturated fatty acids. The inhibition of proline uptake (and that of the other Na+-dependent amino acids) by oleic acid was overcome by the addition of serum albumin and the data presented further indicate that the previously reported stimulation of proline uptake by albumin could be related to its fatty acid binding properties.