Opposing effects of genetic variation in MTCH2 for obesity versus heart failure.

Genetic variation in genes regulating metabolism may be advantageous in some settings but not others. The non-failing adult heart relies heavily on fatty acids as a fuel substrate and source of ATP. In contrast, the failing heart favors glucose as a fuel source. A bootstrap analysis for genes with deviant allele frequencies in cardiomyopathy cases versus controls identified the MTCH2 gene as having unusual variation. MTCH2 encodes an outer mitochondrial membrane protein, and prior genome-wide studies associated MTCH2 variants with body mass index, consistent with its role in metabolism. We identified the referent allele of rs1064608 (p.Pro290) as being overrepresented in cardiomyopathy cases compared to controls, and linkage disequilibrium analysis associated this variant with the MTCH2 cis eQTL rs10838738 and lower MTCH2 expression. To evaluate MTCH2, we knocked down Mtch in Drosophila heart tubes which produced a dilated and poorly functioning heart tube, reduced adiposity and shortened life span. Cardiac Mtch mutants generated more lactate at baseline, and they displayed impaired oxygen consumption in the presence of glucose but not palmitate. Treatment of cardiac Mtch mutants with dichloroacetate, a pyruvate dehydrogenase kinase inhibitor, reduced lactate and rescued lifespan. Deletion of MTCH2 in human cells similarly impaired oxygen consumption in the presence of glucose but not fatty acids. These data support a model in which MTCH2 reduction may be favorable when fatty acids are the major fuel source, favoring lean body mass. However, in settings like heart failure, where the heart shifts toward using more glucose, reduction of MTCH2 is maladaptive.

Rare variation in LMNA underlies polycystic ovary syndrome (PCOS) pathogenesis in two independent cohorts.

CONTEXT: Polycystic ovary syndrome (PCOS) is a common, heritable endocrinopathy that is a common cause of anovulatory infertility in reproductive age women. Variants in LMNA cause partial lipodystrophy, a syndrome with overlapping features to PCOS. OBJECTIVE: We tested the hypothesis that rare variation in LMNA contributes to PCOS pathogenesis and selects a lipodystrophy-like subtype of PCOS. DESIGN, SETTING, AND PARTICIPANTS: We sequenced LMNA by targeted sequencing a discovery cohort of 811 PCOS patients and 164 healthy controls. We then analyzed LMNA from whole-exome sequencing (WES) of a replication cohort of 718 PCOS patients and 281 healthy controls. MAIN OUTCOME MEASURES: Variation in the LMNA gene, hormone and lipid profiles of participants. RESULTS: In the discovery cohort, we identified 8 missense variants in 15/811 cases, and 1 variant in 1/172 reproductively healthy controls. There is strong evidence for association between the variants and PCOS compared to gnomAD non-Finnish European population controls (χ2=17, p=3.7x10-5, OR=2.9). In the replication cohort, we identified 11 unique variants in 15/718 cases, and 1 variant in 281 reproductively healthy controls. Again, there is strong evidence for association with population controls (χ2=30.5, p=3.4x10-8, OR= 4.0). In both the discovery and replication cohorts, variants in LMNA identify women with PCOS with high triglycerides and extreme insulin resistance. CONCLUSIONS: Rare missense variation in LMNA is reproducibly associated with PCOS and identifies some individuals with lipodystrophy-like features. The overlap between this PCOS phenotype and genetic partial lipodystrophy syndromes warrants further investigation into additional lipodystrophy genes and their potential in PCOS etiology.

A Natural History Study of Timothy Syndrome.

Timothy syndrome (OMIM #601005) is a rare disease caused by variants in the gene CACNA1C . Timothy syndrome patients were first identified as having a cardiac presentation of Long QT and syndactyly of the fingers and/or toes, and an identical variant in CACNA1C , Gly406Arg. However, since this original identification, more individuals harboring diverse variants in CACNA1C have been identified and have presented with various cardiac and extra-cardiac symptoms. Furthermore, it has remained underexplored whether individuals harboring canonical Gly406Arg variants in mutually exclusive exon 8A (Timothy syndrome 1) or exon 8 (Timothy syndrome 2) have additional symptoms. Here, we describe the first Natural History Study for Timothy syndrome, providing a thorough resource describing the current understanding of disease manifestation in Timothy syndrome patients. Parents of Timothy syndrome children were queried regarding a wide-ranging set of symptoms and features via a survey. Importantly, we find that in addition to cardiac concerns, Timothy syndrome patients commonly share extra-cardiac features including neurodevelopmental impairments, hypoglycemia, and respiratory problems. Our work expands the current understanding of the disorder to better inform the care of Timothy syndrome patients.

Distinct mechanoreceptor pezo-1 isoforms modulate food intake in the nematode Caenorhabditis elegans.

Two PIEZO mechanosensitive cation channels, PIEZO1 and PIEZO2, have been identified in mammals, where they are involved in numerous sensory processes. While structurally similar, PIEZO channels are expressed in distinct tissues and exhibit unique properties. How different PIEZOs transduce force, how their transduction mechanism varies, and how their unique properties match the functional needs of the tissues they are expressed in remain all-important unanswered questions. The nematode Caenorhabditis elegans has a single PIEZO ortholog (pezo-1) predicted to have 12 isoforms. These isoforms share many transmembrane domains but differ in those that distinguish PIEZO1 and PIEZO2 in mammals. We used transcriptional and translational reporters to show that putative promoter sequences immediately upstream of the start codon of long pezo-1 isoforms predominantly drive green fluorescent protein (GFP) expression in mesodermally derived tissues (such as muscle and glands). In contrast, sequences upstream of shorter pezo-1 isoforms resulted in GFP expression primarily in neurons. Putative promoters upstream of different isoforms drove GFP expression in different cells of the same organs of the digestive system. The observed unique pattern of complementary expression suggests that different isoforms could possess distinct functions within these organs. We used mutant analysis to show that pharyngeal muscles and glands require long pezo-1 isoforms to respond appropriately to the presence of food. The number of pezo-1 isoforms in C. elegans, their putative differential pattern of expression, and roles in experimentally tractable processes make this an attractive system to investigate the molecular basis for functional differences between members of the PIEZO family of mechanoreceptors.

Update on the Molecular Genetics of Timothy Syndrome.

Timothy Syndrome (TS) (OMIM #601005) is a rare autosomal dominant syndrome caused by variants in CACNA1C, which encodes the α1C subunit of the voltage-gated calcium channel Cav1.2. TS is classically caused by only a few different genetic changes and characterized by prolonged QT interval, syndactyly, and neurodevelopmental delay; however, the number of identified TS-causing variants is growing, and the resulting symptom profiles are incredibly complex and variable. Here, we aim to review the genetic and clinical findings of all published case reports of TS to date. We discuss multiple possible mechanisms for the variability seen in clinical features across these cases, including mosaicism, genetic background, isoform complexity of CACNA1C and differential expression of transcripts, and biophysical changes in mutant CACNA1C channels. Finally, we propose future research directions such as variant validation, in vivo modeling, and natural history characterization.

Caenorhabditis elegans for rare disease modeling and drug discovery: strategies and strengths.

Although nearly 10% of Americans suffer from a rare disease, clinical progress in individual rare diseases is severely compromised by lack of attention and research resources compared to common diseases. It is thus imperative to investigate these diseases at their most basic level to build a foundation and provide the opportunity for understanding their mechanisms and phenotypes, as well as potential treatments. One strategy for effectively and efficiently studying rare diseases is using genetically tractable organisms to model the disease and learn about the essential cellular processes affected. Beyond investigating dysfunctional cellular processes, modeling rare diseases in simple organisms presents the opportunity to screen for pharmacological or genetic factors capable of ameliorating disease phenotypes. Among the small model organisms that excel in rare disease modeling is the nematode Caenorhabditis elegans. With a staggering breadth of research tools, C. elegans provides an ideal system in which to study human disease. Molecular and cellular processes can be easily elucidated, assayed and altered in ways that can be directly translated to humans. When paired with other model organisms and collaborative efforts with clinicians, the power of these C. elegans studies cannot be overstated. This Review highlights studies that have used C. elegans in diverse ways to understand rare diseases and aid in the development of treatments. With continuing and advancing technologies, the capabilities of this small round worm will continue to yield meaningful and clinically relevant information for human health.

An Expanded Role for the RFX Transcription Factor DAF-19, with Dual Functions in Ciliated and Nonciliated Neurons.

Regulatory Factor X (RFX) transcription factors (TFs) are best known for activating genes required for ciliogenesis in both vertebrates and invertebrates. In humans, eight RFX TFs have a variety of tissue-specific functions, while in the worm Caenorhabditis elegans, the sole RFX gene, daf-19, encodes a set of nested isoforms. Null alleles of daf-19 confer pleiotropic effects including altered development with a dauer constitutive phenotype, complete absence of cilia and ciliary proteins, and defects in synaptic protein maintenance. We sought to identify RFX/daf-19 target genes associated with neuronal functions other than ciliogenesis using comparative transcriptome analyses at different life stages of the worm. Subsequent characterization of gene expression patterns revealed one set of genes activated in the presence of DAF-19 in ciliated sensory neurons, whose activation requires the daf-19c isoform, also required for ciliogenesis. A second set of genes is downregulated in the presence of DAF-19, primarily in nonsensory neurons. The human orthologs of some of these neuronal genes are associated with human diseases. We report the novel finding that daf-19a is directly or indirectly responsible for downregulation of these neuronal genes in C. elegans by characterizing a new mutation affecting the daf-19a isoform (tm5562) and not associated with ciliogenesis, but which confers synaptic and behavioral defects. Thus, we have identified a new regulatory role for RFX TFs in the nervous system. The new daf-19 candidate target genes we have identified by transcriptomics will serve to uncover the molecular underpinnings of the pleiotropic effects that daf-19 exerts on nervous system function.