NK cell defects in X-linked pigmentary reticulate disorder.

X-linked reticulate pigmentary disorder (XLPDR, Mendelian Inheritance in Man #301220) is a rare syndrome characterized by recurrent infections and sterile multiorgan inflammation. The syndrome is caused by an intronic mutation in POLA1, the gene encoding the catalytic subunit of DNA polymerase-α (Pol-α), which is responsible for Okazaki fragment synthesis during DNA replication. Reduced POLA1 expression in this condition triggers spontaneous type I interferon expression, which can be linked to the autoinflammatory manifestations of the disease.

Sex-chromosome dosage effects on gene expression in humans.

A fundamental question in the biology of sex differences has eluded direct study in humans: How does sex-chromosome dosage (SCD) shape genome function? To address this, we developed a systematic map of SCD effects on gene function by analyzing genome-wide expression data in humans with diverse sex-chromosome aneuploidies (XO, XXX, XXY, XYY, and XXYY). For sex chromosomes, we demonstrate a pattern of obligate dosage sensitivity among evolutionarily preserved X-Y homologs and update prevailing theoretical models for SCD compensation by detecting X-linked genes that increase expression with decreasing X- and/or Y-chromosome dosage. We further show that SCD-sensitive sex-chromosome genes regulate specific coexpression networks of SCD-sensitive autosomal genes with critical cellular functions and a demonstrable potential to mediate previously documented SCD effects on disease.

The predictors of perceived social support among former foster youth.

Based on a 5-wave panel survey of 732 foster youth, the current study examined the respective relationships between foster youths' individual characteristics, youths' social connections with individuals and formal institutions, and the development of perceived social support across the transition to adulthood. Several youth characteristics - including self-reported delinquency and attachment insecurity - were found to be statistically significantly associated with perceived social support. Attachment insecurity also appeared to mediate the relationships between social support and several other youth-level characteristics, including prior placement disruptions and placement with relatives.

Identification of 15 novel partial SHOX deletions and 13 partial duplications, and a review of the literature reveals intron 3 to be a hotspot region.

Short stature homeobox gene (SHOX) is located in the pseudoautosomal region 1 of the sex chromosomes. It encodes a transcription factor implicated in the skeletal growth. Point mutations, deletions or duplications of SHOX or its transcriptional regulatory elements are associated with two skeletal dysplasias, Léri-Weill dyschondrosteosis (LWD) and Langer mesomelic dysplasia (LMD), as well as in a small proportion of idiopathic short stature (ISS) individuals.

DNA polymerase-α regulates the activation of type I interferons through cytosolic RNA:DNA synthesis.

Aberrant nucleic acids generated during viral replication are the main trigger for antiviral immunity, and mutations that disrupt nucleic acid metabolism can lead to autoinflammatory disorders. Here we investigated the etiology of X-linked reticulate pigmentary disorder (XLPDR), a primary immunodeficiency with autoinflammatory features. We discovered that XLPDR is caused by an intronic mutation that disrupts the expression of POLA1, which encodes the catalytic subunit of DNA polymerase-α.

Sim1 inhibits bone formation by enhancing the sympathetic tone in male mice.

Single-minded 1 (Sim1) is a basic helix-loop-helix Per-Arnt-Sim transcription factor that is important for neuronal development in the hypothalamus. Loss-of-function mutation of Sim1 causes early-onset obesity. However, it is unknown whether and how Sim1 regulates bone remodeling.

Inducible neuronal inactivation of Sim1 in adult mice causes hyperphagic obesity.

Germline haploinsufficiency of human or mouse Sim1 is associated with hyperphagic obesity. Sim1 encodes a transcription factor required for proper formation of the paraventricular (PVN), supraoptic, and anterior periventricular hypothalamic nuclei. Sim1 expression persists in these neurons in adult mice, raising the question of whether it plays a physiologic role in regulation of energy balance.

Hyperphagia: current concepts and future directions proceedings of the 2nd international conference on hyperphagia.

Objective: Hyperphagia is a central feature of inherited disorders (e.g., Prader-Willi Syndrome) in which obesity is a primary phenotypic component.

Screening and familial characterization of copy-number variations in NR5A1 in 46,XY disorders of sex development and premature ovarian failure.

The NR5A1 gene encodes for steroidogenic factor 1, a nuclear receptor that regulates proper adrenal and gonadal development and function. Mutations identified by NR5A1 sequencing have been associated with disorders of sex development (DSD), ranging from sex reversal to severe hypospadias in 46,XY patients and premature ovarian failure (POF) in 46,XX patients. Previous reports have identified four families with a history of both 46,XY DSD and 46,XX POF carrying segregating NR5A1 sequence mutations.

Effect of rosiglitazone on survival in patients with diabetes mellitus treated for coronary artery disease.

Objectives: The purpose of this study was to assess the impact of rosiglitazone on survival in patients with diabetes mellitus (DM) and coronary artery disease (CAD).

Methods: We carried out a drug-exposure analysis in 801 patients with DM and CAD in a cardiac catheterization laboratory registry (490 patients treated with a percutaneous coronary intervention, 224 patients treated with coronary artery bypass grafting, and 87 patients treated with medication alone).

Results: A total of 193 patients (24.

Behavioral and social phenotypes in boys with 47,XYY syndrome or 47,XXY Klinefelter syndrome.

Objective: To contrast the behavioral and social phenotypes including a screen for autistic behaviors in boys with 47,XYY syndrome (XYY) or 47,XXY Klinefelter syndrome (KS) and controls and investigate the effect of prenatal diagnosis on the phenotype.

Methods: Patients included 26 boys with 47,XYY, 82 boys with KS, and 50 control boys (ages 4-15 years). Participants and parents completed a physical examination, behavioral questionnaires, and intellectual assessments.

Submicroscopic chromosomal copy number variations identified in children with hypoplastic left heart syndrome.

Hypoplastic left heart syndrome (HLHS), one of the most severe types of congenital heart disease (CHD), results in significant morbidity and mortality despite surgical palliation. The etiology of HLHS is unknown, but evidence supports genetic contributors. The authors hypothesized that submicroscopic chromosomal abnormalities exist in individuals with HLHS and are more frequent in those with additional birth defects.

Coronary stent thrombosis in patients undergoing multidigit replantation.

Objective: The development of drug-eluting stents has decreased the rate of in-stent restenosis. However, there have been reports of late stent thrombosis in patients with drug-eluting stents, especially when dual antiplatelet therapy is interrupted. The high mortality rate associated with cardiac stent thrombosis has led to recent recommendations regarding duration of antiplatelet therapy as well as timing of elective surgery in patients with both drug-eluting stents and bare metal stents.

Human balanced translocation and mouse gene inactivation implicate Basonuclin 2 in distal urethral development.

We studied a man with distal hypospadias, partial anomalous pulmonary venous return, mild limb-length inequality and a balanced translocation involving chromosomes 9 and 13. To gain insight into the etiology of his birth defects, we mapped the translocation breakpoints by high-resolution comparative genomic hybridization (CGH), using chromosome 9- and 13-specific tiling arrays to analyze genetic material from a spontaneously aborted fetus with unbalanced segregation of the translocation. The chromosome 13 breakpoint was ∼400  kb away from the nearest gene, but the chromosome 9 breakpoint fell within an intron of Basonuclin 2 (BNC2), a gene that encodes an evolutionarily conserved nuclear zinc-finger protein.

Unconventional wisdom about the obesity epidemic.

Diet and sedentary lifestyle, interacting with "thrifty" genes, are widely accepted as the principal cause of the current global obesity epidemic. However, a number of alternative etiologies for obesity have been proposed, including "drifty" genes, viruses, bacteria, environmental toxins, social network effects, maternal imprinting, sleep deprivation, and others. These Grand Rounds reviews the background of some of these unconventional ideas and evidence for or against their roles in the obesity epidemic.

UBE2A deficiency syndrome: Mild to severe intellectual disability accompanied by seizures, absent speech, urogenital, and skin anomalies in male patients.

We describe three patients with a comparable deletion encompassing SLC25A43, SLC25A5, CXorf56, UBE2A, NKRF, and two non-coding RNA genes, U1 and LOC100303728. Moderate to severe intellectual disability (ID), psychomotor retardation, severely impaired/absent speech, seizures, and urogenital anomalies were present in all three patients. Facial dysmorphisms include ocular hypertelorism, synophrys, and a depressed nasal bridge.

A serotonin and melanocortin circuit mediates D-fenfluramine anorexia.

D-Fenfluramine (D-Fen) increases serotonin (5-HT) content in the synaptic cleft and exerts anorexigenic effects in animals and humans. However, the neural circuits that mediate these effects are not fully identified. To address this issue, we assessed the efficacy of D-Fen-induced hypophagia in mouse models with manipulations of several genes in selective populations of neurons.

Postnatal Sim1 deficiency causes hyperphagic obesity and reduced Mc4r and oxytocin expression.

Single-minded 1 (SIM1) mutations are one of the few known causes of nonsyndromic monogenic obesity in both humans and mice. Although the role of Sim1 in the formation of the hypothalamus has been described, its postdevelopmental, physiological functions have not been well established. Here we demonstrate that postnatal CNS deficiency of Sim1 is sufficient to cause hyperphagic obesity.

An extra X or Y chromosome: contrasting the cognitive and motor phenotypes in childhood in boys with 47,XYY syndrome or 47,XXY Klinefelter syndrome.

Objective: The goal of this study was to contrast the cognitive phenotypes in boys with 47,XYY (XYY) karyotype and boys with 47,XXY karyotype [Klinefelter syndrome, (KS)], who share an extra copy of the X-Y pseudoautosomal region but differ in their dosage of strictly sex-linked genes.

Methods: Neuropsychological evaluation of general cognitive ability, language, memory, attention, visual-spatial abilities, visual-motor skills, and motor function.

Results: Study cohort: 21 boys with 47,XYY and 93 boys with 47,XXY (KS), age 4-17 years, and 36 age-matched control boys.

Effect of growth hormone therapy on severe short stature and skeletal deformities in a patient with combined Turner syndrome and Langer mesomelic dysplasia.

Background: Homozygous mutation of the short stature homeobox-containing gene, SHOX, results in Langer mesomelic dysplasia (LMD). Our case presented with severe short stature and skeletal deformities with Turner syndrome (TS) and a SHOX gene abnormality due to a downstream allele deletion in her normal X chromosome. Medical literature review did not reveal similar cases that were treated with GH therapy.

Optimizing antithrombotic strategies in patients with concomitant indications for warfarin undergoing coronary artery stenting.

The current standard in coronary artery stenting is dual antiplatelet therapy with aspirin and clopidogrel, with the duration of therapy primarily based on the use of bare metal or drug-eluting stents. The expanding patient population in whom oral anticoagulation and dual antiplatelet therapy may be indicated poses unique challenges in navigating the delicate balance between the efficacy of these therapies and bleeding risk. Although limited data exist, meaningful recommendations can be made involving individualization of these and other therapies (such as cilostazol) based on the perceived risk of thrombotic stent complications, indication for oral anticoagulant therapy, and bleeding risk.

Computing power of quantitative trait locus association mapping for haploid loci.

Background: Statistical power calculations are a critical part of any study design for gene mapping. Most calculations assume that the locus of interest is biallelic. However, there are common situations in human genetics such as X-linked loci in males where the locus is haploid.

MODY-like diabetes associated with an apparently balanced translocation: possible involvement of MPP7 gene and cell polarity in the pathogenesis of diabetes.

Background: Characterization of disease-associated balanced translocations has led to the discovery of genes responsible for many disorders, including syndromes that include various forms of diabetes mellitus. We studied a man with unexplained maturity onset diabetes of the young (MODY)-like diabetes and an apparently balanced translocation [46,XY,t(7;10)(q22;p12)] and sought to identify a novel diabetes locus by characterizing the translocation breakpoints.

Results: Mutations in coding exons and splice sites of known MODY genes were first ruled out by PCR amplification and DNA sequencing.