Prader-Willi syndrome: an update on obesity and endocrine problems

Prader-Willi syndrome (PWS) is a rare complex genetic disorder that results from a lack of expression of the paternally inherited chromosome 15q11-q13. PWS is characterized by hypotonia and feeding difficulty in early infancy and development of morbid obesity aggravated by uncontrolled hyperphagia after childhood and adolescent. Dysmorphic facial features, delayed motor and language development, various degrees of cognitive impairment, and behavioral problems are common in PWS. Without early, intensive nutritional therapy along with behavioral modification, PWS patients develop severe obesity associated with type 2 diabetes, obstructive sleep apnea, right-side heart failure, and other obesity-related metabolic complications. Hypothalamic dysfunction in PWS can lead to several endocrine disorders, including short stature with growth hormone deficiency, hypothyroidism, central adrenal insufficiency, and hypogonadism. In this review, we discuss the natural history of PWS and the mechanisms of hyperphagia and obesity. We also provide an update on obesity treatments and recommendations for screening and monitoring of various endocrine problems that can occur in PWS.

Patient-derived gene and protein expression signatures of NGLY1 deficiency

N-Glycanase 1 (NGLY1) deficiency is a rare and complex genetic disorder. Although recent studies have shed light on the molecular underpinnings of NGLY1 deficiency, a systematic characterization of gene and protein expression changes in patient-derived cells has been lacking. Here, we performed RNA-sequencing and mass spectrometry to determine the transcriptomes and proteomes of 66 cell lines representing 4 different cell types derived from 14 NGLY1 deficient patients and 17 controls. Although NGLY1 protein levels were up to 9.5-fold downregulated in patients compared to parents, residual and likely non-functional NGLY1 protein was detectable in all patient-derived lymphoblastoid cell lines. Consistent with the role of NGLY1 as a regulator of the transcription factor Nrf1, we observed a cell type-independent downregulation of proteasomal genes in NGLY1 deficient cells. In contrast, genes involved in ribosome biogenesis and mRNA processing were upregulated in multiple cell types. In addition, we observed cell type-specific effects. For example, genes and proteins involved in glutathione synthesis, such as the glutamate-cysteine ligase subunits GCLC and GCLM, were downregulated specifically in lymphoblastoid cells. We provide a web application that enables access to all results generated in this study at https://apps.embl.de/ngly1browser. This resource will guide future studies of NGLY1 deficiency in directions that are most relevant to patients.

Heritability and Genomic Architecture of Episodic Exercise-Induced Collapse in Border Collies

An episodic nervous system disorder triggered by strenuous exercise, termed border collie collapse (BCC), exists in border collies and related breeds. The genetic basis of BCC is unknown but is believed to be a complex genetic disorder. Our goal was to estimate the heritability (h2SNP) of BCC, define its underlying genetic architecture, and identify associated genomic loci using dense whole-genome single-nucleotide polymorphism (SNP) genotyping data. Genotype data were obtained for ~440,000 SNPs from 343 border collies (168 BCC cases and 175 controls). h2SNP was calculated to be 49–61% depending on the estimated BCC prevalence. A total of 2407 SNPs across the genome accounted for nearly all the h2SNP of BCC, with an estimated 2003 SNPs of small effect, 349 SNPs of moderate effect, and 56 SNPs of large effect. Genome-wide association analyses identified significantly associated loci on chromosomes 1, 6, 11, 20, and 28, which accounted for ~5% of the total BCC h2SNP. We conclude that BCC is a moderately- to highly- heritable complex polygenetic disease resulting from contributions from hundreds to thousands of genetic variants with variable effect sizes. Understanding how much the BCC phenotype is determined by genetics and whether major gene mutations are likely to exist inform veterinarians and working/stock dog communities of the true nature of this condition.

Identification of a Rare Novel KMT2C Mutation That Presents with Schizophrenia in a Multiplex Family

Schizophrenia is a complex genetic disorder involving many common variants with modest effects and rare mutations with high penetrance. Rare mutations associated with schizophrenia are highly heterogeneous and private for affected individuals and families. Identifying such mutations can help establish the molecular diagnosis, elucidate the pathogenesis, and provide helpful genetic counseling for affected patients and families. We performed a whole-exome sequencing analysis to search for rare pathogenic mutations co-segregating with schizophrenia transmitted in a dominant inheritance in a two-generation multiplex family. We identified a rare missense mutation H1574R (Histidine1574Arginine, rs199796552) of KMT2C (lysine methyltransferase 2C) co-segregating with affected members in this family. The mutation is a novel deleterious mutation of KMT2C, not reported before in the literature. The KMT2C encodes a histone 3 lysine 4 (H3K4)-specific methyltransferase and involves epigenetic regulation of brain gene expression. Mutations of KMT2C have been found in neurodevelopmental disorders, such as Kleefstra syndrome, intellectual disability, and autism spectrum disorders. Our finding suggests that schizophrenia might be one of the clinical phenotype spectra of KMT2C mutations, and KMT2C might be a novel risk gene for schizophrenia. Nevertheless, the co-segregation of this mutation with schizophrenia in this family might also be due to chance; functional assays of this mutation are needed to address this issue.

Novel DYRK1A Inhibitor Rescues Learning and Memory Deficits in a Mouse Model of Down Syndrome

Down syndrome (DS) is a complex genetic disorder associated with substantial physical, cognitive, and behavioral challenges. Due to better treatment options for the physical co-morbidities of DS, the life expectancy of individuals with DS is beginning to approach that of the general population. However, the cognitive deficits seen in individuals with DS still cannot be addressed pharmacologically. In young individuals with DS, the level of intellectual disability varies from mild to severe, but cognitive ability generally decreases with increasing age, and all individuals with DS have early onset Alzheimer’s disease (AD) pathology by the age of 40. The present study introduces a novel inhibitor for the protein kinase DYRK1A, a key controlling kinase whose encoding gene is located on chromosome 21. The novel inhibitor is well characterized for use in mouse models and thus represents a valuable tool compound for further DYRK1A research.

Ellis-van Creveld Syndrome

Ellis-van Creveld syndrome, also known as chondroectodermal dysplasia, is a complex genetic disorder caused by the mutation of particular genes, characterized by dwarfism, polydactyly, abnormal nail structure, and dental malformations. Dental manifestations include enamel hypoplasia and hypodontia. Patients with Ellis-van Creveld syndrome may also have heart defects that would require specific diagnostic tools. The exact prevalence of this disorder remains poorly investigated because most risk groups are the Amish population, who refuse to share personal information voluntarily. We hereby present a case report of an eighteen-year-old young woman who presented with the chief complaint of poor appearance of teeth. The medical history includes ventricular hypertrophy and epilepsy. The patient had mandibular natal teeth that were removed. The first line of treatment was offered when the girl was seven, and standard check-ups and orthodontic manipulations were made within the last ten years. Overall, this case proves the importance of radiographic and physical examination, along with the multidisciplinary cooperation of dentists, surgeons, orthodontists, anesthetists, and cardiologists. Keywords: Dental enamel hypoplasia; Dwarfism; Ellis-van Creveld syndrome; Epilepsy; Malformed nails; Natal teeth

Clinical Profile of Polycystic Ovarian Syndrome Patients In Tertiary Care Hospital

ABSTRACT: Background: Polycystic ovarian syndrome (PCOS)is common gynecological endocrinopathy characterized by chronic anovulation and hyperandrogenism affecting 5-10% of women worldwide. It is a heterogenous, multifactorial, complex genetic disorder with uncertain etiology and is one of the most common treatable cause of infertility. AIM: To study the various clinical presentations in polycystic ovarian syndrome. MATERIALS AND METHODS: Present study is cross sectional observational study carried out in tertiary care centre. This study was performed in the Out Patient Department of Obstetrics and Gynecology. RESULTS: The mean age of 41 patients in the study was 23.6 years. Most common presenting symptom in patients is menstrual irregularities (89%) followed by infertility and hirsutism. USG (abdo+pelvis) showing polycystic ovarian syndrome ovaries. Around 39% patients with PCOS developed insulin resistance. KEYWORDS: - Amenorrhea, Infertility, Oligomenorrhea, Polycystic Ovarian Syndrome.

Characterization of USH1C/harmonin in the human retina provides insights into pathophysiology and therapy options for Usher syndrome

Human Usher syndrome (USH) is a complex genetic disorder that comprises three clinical subtypes USH1, USH2 and USH3 and the most common form of hereditary combined deaf-blindness. Since rodent USH1 models do not reflect the ocular phenotype observed in human patients to date only little is known about the pathophysiology of USH1 in the human eye. The USH1C gene is heavily alternatively spliced and encodes for numerous harmonin isoforms that function as scaffold proteins and organizer of the USH interactome. RNA-seq analysis of USH1C revealed harmonin a1 as the most abundant transcript of USH1C in the human retina. Bulk mRNA-seq and Western blots confirmed abundant expression of harmonin in Müller glia cells (MGCs) and retinal neurons. We located harmonin in the terminal endfeet and apical microvilli of MGCs and in photoreceptor cells (PRCs), particularly in cone synapses and outer segments of rods as well as at adhesive junctions between both, MGCs and PRCs in the outer limiting membrane (OLM). We evidenced the interaction of harmonin with OLM molecules and rhodopsin in PRCs. We correlate the identified harmonin subcellular expression and colocalization with the clinical phenotype observed in USH1C patients. Furthermore, we demonstrate a phenotype in primary cilia in patient-derived fibroblasts which we were able to revert by gene addition of harmonin a1. Our data provide novel insights for retinal cell biology, USH1C pathophysiology and subsequent gene therapy development.

Patient-derived gene and protein expression signatures of NGLY1 deficiency

N-Glycanase 1 (NGLY1) deficiency is a rare and complex genetic disorder. Although recent studies have shed light on the molecular underpinnings of NGLY1 deficiency, a systematic characterization of gene and protein expression changes in patient-derived cells has been lacking. Here, we performed RNA-sequencing and mass spectrometry to determine the transcriptomes and proteomes of 66 cell lines representing 4 different cell types derived from 14 NGLY1 deficient patients and 17 controls. While gene and protein expression levels agreed well with each other, expression differences were more pronounced at the protein level. Although NGLY1 protein levels were up to 9.5-fold downregulated in patients compared to parent controls, depending on the genotype, NGLY1 protein was still detectable in all patient- derived lymphoblastoid cell lines. Consistent with the role of NGLY1 as a regulator of the transcription factor Nrf1, we observed a cell type-independent downregulation of proteasomal genes in NGLY1 deficient cells. In contrast, genes involved in ribosomal mRNA processing were upregulated in multiple cell types. In addition, we observed cell type-specific effects. For example, genes and proteins involved in glutathione synthesis, such as the glutamate-cystein ligase subunits GCLC and GCLM, were downregulated specifically in lymphoblastoid cells. We provide a web application that enables access to all results generated in this study at https://apps.embl.de/ngly1browser. This resource will guide future studies of NGLY1 deficiency in directions that are most relevant to patients.

Two Monogenetic Disorders, Activated PI3-Kinase-δ Syndrome 2 and Smith–Magenis Syndrome, in One Patient: Case Report and a Literature Review of Neurodevelopmental Impact in Primary Immunodeficiencies Associated With Disturbed PI3K Signaling

Activated PI3-kinase-δ syndrome 2 (APDS2) is caused by autosomal dominant mutations in the PIK3R1 gene encoding the p85α, p55α, and p50α regulatory subunits. Most diagnosed APDS2 patients carry mutations affecting either the splice donor or splice acceptor sites of exon 11 of the PIK3R1 gene responsible for an alternative splice product and a shortened protein. The clinical presentation of APDS2 patients is highly variable, ranging from mild to profound combined immunodeficiency features as massive lymphoproliferation, increased susceptibility to bacterial and viral infections, bronchiectasis, autoimmune manifestations, and occurrence of cancer. Non-immunological features such as growth retardation and neurodevelopmental delay have been reported for APDS2 patients. Here, we describe a patient suffering from an APDS2 associated with a Smith–Magenis syndrome (SMS), a complex genetic disorder affecting, among others, neurological manifestations and review the literature describing neurodevelopmental impacts in APDS2 and other PIDs/monogenetic disorders associated with dysregulated PI3K signaling.