Background: TheLatrophilin 3(LPHN3) gene (recently renamedAdhesion G protein‐coupled receptor L3 (ADGRL3)) has been linked to susceptibility to attention deficit/hyperactivity disorder (ADHD) and vulnerability to addiction. However, its role and function are not well understood as there are no known functional variants.Methods: To characterize the function of this little known gene, we phenotypedLphn3null mice. We assessed motivation for food reward and working memory via instrumental responding tasks, motor coordination via rotarod, and depressive‐like behavior via forced swim. We also measured neurite outgrowth of primary hippocampal and cortical neuron cultures. Standard blood chemistries and blood counts were performed. Finally, we also evaluated the transcriptome in several brain regions.Results: Behaviorally, loss ofLphn3increases both reward motivation and activity levels.Lphn3null mice display significantly greater instrumental responding for food than wild‐type mice, particularly under high response ratios, and swim incessantly during a forced swim assay. However, loss ofLphn3does not interfere with working memory or motor coordination. Primary hippocampal and cortical neuron cultures demonstrate that null neurons display comparatively enhanced neurite outgrowth after 2 and 3 days in vitro. Standard blood chemistry panels reveal that nulls have low serum calcium levels. Finally, analysis of the transcriptome from prefrontal cortical, striatal, and hippocampal tissue at different developmental time points shows that loss ofLphn3results in genotype‐dependent differential gene expression (DGE), particularly for cell adhesion molecules and calcium signaling proteins. Much of theDGEis attenuated with age, and is consistent with the idea thatADHDis associated with delayed cortical maturation.Conclusions: Transcriptome changes likely affect neuron structure and function, leading to behavioral anomalies consistent with bothADHDand addiction phenotypes. The data should further motivate analyses ofLphn3function in the developmental timing of altered gene expression and calcium signaling, and their effects on neuronal structure/function during development.

Significant advances in biotechnology have led to the development of a number of different mutation-directed therapies. Some of these techniques have matured to a level that has allowed testing in clinical trials, but few have made it to approval by drug-regulatory bodies for the treatment of specific diseases. While there are still various hurdles to be overcome, recent success stories have proven the potential power of mutation-directed therapies and have fueled the hope of finding therapeutics for other genetic disorders. In this review, we summarize the state-of-the-art of various therapeutic approaches and assess their applicability to the genetic disorder neurofibromatosis type I (NF1). NF1 is caused by the loss of function of neurofibromin, a tumor suppressor and downregulator of the Ras signaling pathway. The condition is characterized by a variety of phenotypes and includes symptoms such as skin spots, nervous system tumors, skeletal dysplasia, and others. Hence, depending on the patient, therapeutics may need to target different tissues and cell types. While we also discuss the delivery of therapeutics, in particular via viral vectors and nanoparticles, our main focus is on therapeutic techniques that reconstitute functional neurofibromin, most notably cDNA replacement, CRISPR-based DNA repair, RNA repair, antisense oligonucleotide therapeutics including exon skipping, and nonsense suppression.

Numerous successful gene-targeted therapies are arising for the treatment of a variety of rare diseases. At the same time, current treatment options for neurofibromatosis 1 and schwannomatosis are limited and do not directly address loss of gene/protein function. In addition, treatments have mostly focused on symptomatic tumors, but have failed to address multisystem involvement in these conditions. Gene-targeted therapies hold promise to address these limitations. However, despite intense interest over decades, multiple preclinical and clinical issues need to be resolved before they become a reality. The optimal approaches to gene-, mRNA-, or protein restoration and to delivery to the appropriate cell types remain elusive. Preclinical models that recapitulate manifestations of neurofibromatosis 1 and schwannomatosis need to be refined. The development of validated assays for measuring neurofibromin and merlin activity in animal and human tissues will be critical for early-stage trials, as will the selection of appropriate patients, based on their individual genotypes and risk/benefit balance. Once the safety of gene-targeted therapy for symptomatic tumors has been established, the possibility of addressing a wide range of symptoms, including non-tumor manifestations, should be explored. As preclinical efforts are underway, it will be essential to educate both clinicians and those affected by neurofibromatosis 1/schwannomatosis about the risks and benefits of gene-targeted therapy for these conditions.

The main characteristic of attention deficit/hyperactivity disorder (ADHD) is a persistent pattern of inattention and/or hyperactivity-impulsivity which is more frequent and severe than is usually expected in individuals at a comparable level of development. ADHD is estimated to affect approximately 5.29% of school-aged children and is therefore the most common childhood onset psychological disorder. A conservative estimate of the annual societal cost of illness for ADHD in childhood and adolescence is USD 42.5 billion in the U.S. alone. Global sales of ADHD medicines could reach USD 4.3 billion by 2012. Despite the prevalence, high heritability and costs of ADHD, biological markers do not exist. Such biomarkers are in high demand as they would help eliminate the subjective diagnoses based on interviews and potentially allow for earlier diagnosis and personalized medicine. Lack of markers likely stems from several factors that complicate ADHD research and the assessment of pharmacological responses. This review analyses complicating factors in defining ADHD phenotype and etiology, identifying specific diagnostic markers and the difficulties in the assessment of pharmacogenomic markers. The dopamine transporter (DAT1) genotype and methylphenidate (MPH) response are detailed as an example of a biomarker. A recent report of a novel ADHD gene and its possible role as a biomarker is explored. Finally, suggestions for strategies and study designs for future research for the definition of effective ADHD biomarkers are made.