A splice site variant in MADD affects hormone expression in pancreatic β cells and pituitary gonadotropes.

MAPK activating death domain (MADD) is a multifunctional protein regulating small GTPases RAB3 and RAB27, MAPK signaling, and cell survival. Polymorphisms in the MADD locus are associated with glycemic traits, but patients with biallelic variants in MADD manifest a complex syndrome affecting nervous, endocrine, exocrine, and hematological systems. We identified a homozygous splice site variant in MADD in 2 siblings with developmental delay, diabetes, congenital hypogonadotropic hypogonadism, and growth hormone deficiency.

Deciphering the Transcriptional Landscape of Human Pluripotent Stem Cell-Derived GnRH Neurons: The Role of Wnt Signaling in Patterning the Neural Fate.

Hypothalamic gonadotropin-releasing hormone (GnRH) neurons lay the foundation for human development and reproduction; however, the critical cell populations and the entangled mechanisms underlying the development of human GnRH neurons remain poorly understood. Here, by using our established human pluripotent stem cell-derived GnRH neuron model, we decoded the cellular heterogeneity and differentiation trajectories at the single-cell level. We found that a glutamatergic neuron population, which generated together with GnRH neurons, showed similar transcriptomic properties with olfactory sensory neuron and provided the migratory path for GnRH neurons.

Characterization of the human GnRH neuron developmental transcriptome using a -TdTomato reporter line in human pluripotent stem cells.

Gonadotropin-releasing hormone (GnRH) neurons provide a fundamental signal for the onset of puberty and subsequent reproductive functions by secretion of gonadotropin-releasing hormone. Their disrupted development or function leads to congenital hypogonadotropic hypogonadism (CHH). To model the development of human GnRH neurons, we generated a stable -TdTomato reporter cell line in human pluripotent stem cells (hPSCs) using CRISPR-Cas9 genome editing.

Neuron-Derived Neurotrophic Factor Is Mutated in Congenital Hypogonadotropic Hypogonadism.

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by infertility and the absence of puberty. Defects in GnRH neuron migration or altered GnRH secretion and/or action lead to a severe gonadotropin-releasing hormone (GnRH) deficiency. Given the close developmental association of GnRH neurons with the olfactory primary axons, CHH is often associated with anosmia or hyposmia, in which case it is defined as Kallmann syndrome (KS).

MKRN3 Interacts With Several Proteins Implicated in Puberty Timing but Does Not Influence Expression.

Paternally-inherited loss-of-function mutations in makorin ring finger protein 3 gene () underlie central precocious puberty. To investigate the puberty-related mechanism(s) of in humans, we generated two distinct bi-allelic knock-out human pluripotent stem cell lines, Del 1 and Del 2, and differentiated them into -expressing neurons. Both Del 1 and Del 2 clones could be differentiated into neuronal progenitors and -expressing neurons, however, the relative expression of did not differ from wild type cells ( = NS).

Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis.

Familial growth hormone deficiency provides an opportunity to identify new genetic causes of short stature. Here we combine linkage analysis with whole-genome resequencing in patients with growth hormone deficiency and maternally inherited gingival fibromatosis. We report that patients from three unrelated families harbor either of two missense mutations, c.

Development of Gonadotropin-Releasing Hormone-Secreting Neurons from Human Pluripotent Stem Cells.

Gonadotropin-releasing hormone (GnRH) neurons regulate human puberty and reproduction. Modeling their development and function in vitro would be of interest for both basic research and clinical translation. Here, we report a three-step protocol to differentiate human pluripotent stem cells (hPSCs) into GnRH-secreting neurons.

Quantification assays for total and polyglutamine-expanded huntingtin proteins.

The expansion of a CAG trinucleotide repeat in the huntingtin gene, which produces huntingtin protein with an expanded polyglutamine tract, is the cause of Huntington's disease (HD). Recent studies have reported that RNAi suppression of polyglutamine-expanded huntingtin (mutant HTT) in HD animal models can ameliorate disease phenotypes. A key requirement for such preclinical studies, as well as eventual clinical trials, aimed to reduce mutant HTT exposure is a robust method to measure HTT protein levels in select tissues.

Mobile graphics.

Mobile phones form a ubiquitous graphics platform; over half of the world population uses them. This special issue presents solutions that overcome some of the inherent limitations of these compact computing devices and make use of the fact that they are available at all times, not just at your desk.

Genome-wide linkage scan for loci of musical aptitude in Finnish families: evidence for a major locus at 4q22.

Background: Music perception and performance are comprehensive human cognitive functions and thus provide an excellent model system for studying human behaviour and brain function. However, the molecules involved in mediating music perception and performance are so far uncharacterised.

Objective: To unravel the biological background of music perception, using molecular and statistical genetic approaches.

A dose-response study of total sleep time and the ability to maintain wakefulness.

The apparent connection between sleep debt, performance decrements and workplace accidents has generated a need for feasible vigilance tests that focus on the quantification of daytime sleepiness in occupational settings. The objective of this study was to evaluate the sensitivity of the Maintenance of Wakefulness Test (MWT) to acute sleep deprivation of various doses. Eight healthy female volunteers, mean age 28.

Rescheduling a three shift system at a steel rolling mill: effects of a one hour delay of shift starting times on sleep and alertness in younger and older workers.

Objective: To evaluate a new work schedule at a Finnish steel mill with special attention to effects on older workers. The schedule was designed to improve sleep before the morning shift, and alertness during the morning shift, by delaying shift start and end times.

Methods: Evaluation was by a shiftwork health and safety questionnaire, recordings of work-rest-sleep cycles with activity monitors worn on the wrist, daily diaries, and on site computerised testing of fatigue and alertness by the NIOSH fatigue test battery.

The relationship between EEG delta activity and autonomic activity as measured by SCSB during daytime sleep.

The aim of the present work was to study the applicability of the static-charge-sensitive bed (SCSB) method to sleep studies, by comparing autonomic nervous activity measured with the SCSB and EEG delta activity (0.5-2 Hz). Simultaneous polygraphic and SCSB measurements of the first sleep cycle (110 min) were recorded from seven subjects.