Mutations in cytochrome P450 oxidoreductase (POR) cause a form of congenital adrenal hyperplasia (CAH). We report a novel R550W mutation in POR identified in a 46,XX patient with signs of aromatase ...deficiency.
Analysis of aromatase deficiency from the R550W mutation in POR.
Both the child and the mother had signs of virilization. Ultrasound revealed the presence of uterus and ovaries. No defects in CYP19A1 were found, but further analysis with a targeted Disorders of Sexual Development NGS panel (DSDSeq.V1, 111 genes) on a NextSeq (Illumina) platform in Madrid and Barcelona, Spain, revealed compound heterozygous mutations c.73_74delCT/p.L25FfsTer93 and c.1648C > T/p.R550W in POR. Wild-type and R550W POR were produced as recombinant proteins and tested with multiple cytochrome P450 enzymes at University Children's Hospital, Bern, Switzerland.
POR-R550W showed 41% of the WT activity in cytochrome c and 7.7% activity for reduction of MTT. Assays of CYP19A1 showed a severe loss of activity, and CYP17A1 as well as CYP21A2 activities were also lost by more than 95%. Loss of CYP2C9, CYP2C19, and CYP3A4 activities was observed for the R550W-POR. Predicted adverse effect on aromatase activity as well as a reduction in binding of NADPH was confirmed.
Pathological effects due to POR-R550W were identified, expanding the knowledge of molecular pathways associated with aromatase deficiency. Screening of the POR gene may provide a diagnosis in CAH without defects in genes for steroid metabolizing enzymes.
Noonan syndrome is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart defects and skeletal anomalies. Increased RAS-mitogen-activated protein kinase (MAPK) ...signaling due to PTPN11 and KRAS mutations causes 50% of cases of Noonan syndrome. Here, we report that 22 of 129 individuals with Noonan syndrome without PTPN11 or KRAS mutation have missense mutations in SOS1, which encodes a RAS-specific guanine nucleotide exchange factor. SOS1 mutations cluster at codons encoding residues implicated in the maintenance of SOS1 in its autoinhibited form. In addition, ectopic expression of two Noonan syndrome-associated mutants induces enhanced RAS and ERK activation. The phenotype associated with SOS1 defects lies within the Noonan syndrome spectrum but is distinctive, with a high prevalence of ectodermal abnormalities but generally normal development and linear growth. Our findings implicate gain-of-function mutations in a RAS guanine nucleotide exchange factor in disease for the first time and define a new mechanism by which upregulation of the RAS pathway can profoundly change human development.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Genomic imprinting is an epigenetic process regulated by germline-derived DNA methylation that is resistant to embryonic reprogramming, resulting in parental origin-specific monoallelic gene ...expression. A subset of individuals affected by imprinting disorders (IDs) displays multi-locus imprinting disturbances (MLID), which may result from aberrant establishment of imprinted differentially methylated regions (DMRs) in gametes or their maintenance in early embryogenesis. Here we investigated the extent of MLID in a family harbouring a ZFP57 truncating variant and characterize the interactions between human ZFP57 and the KAP1 co-repressor complex. By ectopically targeting ZFP57 to reprogrammed loci in mouse embryos using a dCas9 approach, we confirm that ZFP57 recruitment is sufficient to protect oocyte-derived methylation from reprogramming. Expression profiling in human pre-implantation embryos and oocytes reveals that unlike in mice, ZFP57 is only expressed following embryonic-genome activation, implying that other KRAB-zinc finger proteins (KZNFs) recruit KAP1 prior to blastocyst formation. Furthermore, we uncover ZNF202 and ZNF445 as additional KZNFs likely to recruit KAP1 to imprinted loci during reprogramming in the absence of ZFP57. Together, these data confirm the perplexing link between KZFPs and imprint maintenance and highlight the differences between mouse and humans in this respect.
MAMLD1 is thought to cause disordered sex development in 46,XY patients. But its role is controversial because some MAMLD1 variants are also detected in normal individuals, several MAMLD1 mutations ...have wild-type activity in functional tests, and the male Mamld1-knockout mouse has normal genitalia and reproduction. Our aim was to search for MAMLD1 variations in 108 46,XY patients with disordered sex development, and to test them functionally. We detected MAMDL1 variations and compared SNP frequencies in controls and patients. We tested MAMLD1 transcriptional activity on promoters involved in sex development and assessed the effect of MAMLD1 on androgen production. MAMLD1 expression in normal steroid-producing tissues and mutant MAMLD1 protein expression were also assessed. Nine MAMLD1 mutations (7 novel) were characterized. In vitro, most MAMLD1 variants acted similarly to wild type. Only the L210X mutation showed loss of function in all tests. We detected no effect of wild-type or MAMLD1 variants on CYP17A1 enzyme activity in our cell experiments, and Western blots revealed no significant differences for MAMLD1 protein expression. MAMLD1 was expressed in human adult testes and adrenals. In conclusion, our data support the notion that MAMLD1 sequence variations may not suffice to explain the phenotype in carriers and that MAMLD1 may also have a role in adult life.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although the prevalence of pediatric obesity is rising, understanding of the perceptions, attitudes, behaviors, and barriers to effective obesity care among Spanish adolescents living with obesity ...(ALwO), their caregivers, and healthcare professionals (HCPs) is lacking. In 2021, the cross-sectional ACTION Teens survey study was conducted in 10 countries; results from the Spanish cohort are presented herein. The survey was completed by 648 ALwO, 644 caregivers, and 251 HCPs in Spain. A total of 25% of ALwO and 43% of caregivers thought that their/their child's weight was normal, and more caregivers than ALwO perceived the ALwO's health to be at least good (95% vs. 59%, respectively). Only 53% of ALwO and 9% of caregivers reported receiving an obesity diagnosis, despite HCPs reporting they provide diagnoses to 87% of ALwO/caregivers. Although 65% of HCPs felt that ALwO may not be comfortable discussing weight, only 26% of ALwO who had discussed weight with an HCP (
= 488) reported not feeling comfortable. Inability to control hunger was a key barrier to ALwO losing weight identified by ALwO/caregivers, but not HCPs. Improved communication between the three groups, a better understanding of barriers to weight loss, and improved health education on obesity are needed in order to enhance obesity care in Spain.
Highlights • This is the first study to estimate the social costs associated with familial (informal) caregiving of children with type 1 diabetes mellitus. • Children with an HbA1c level lower than ...7.5% consume significantly less healthcare resources and have a significantly lower cost than children with an HbA1c level of 7.5% or over. • Children who do not have complications associated with type 1 diabetes consume significantly less healthcare resources and have a significantly lower cost than children with complications. • The time that families devote to diabetes surveillance, glucose control, and other diabetes related care, represents the largest component of the total socioeconomic cost associated with type 1 diabetes in children.
Summary
Background
There is limited evidence regarding the experiences, challenges, and needs of adolescents living with obesity (ALwO), their caregivers, and healthcare professionals (HCPs).
...Objectives
The cross‐sectional, survey‐based global ACTION Teens study aimed to identify perceptions, attitudes, behaviours, and barriers to effective obesity care among ALwO, caregivers of ALwO, and HCPs.
Methods
ALwO (aged 12 to <18 years; N = 5275), caregivers (N = 5389), and HCPs treating ALwO (N = 2323) from 10 countries completed an online survey (August–December 2021).
Results
Most ALwO perceived their weight as above normal (76% vs. 66% of caregivers), were worried about its impact on their health (85% vs. 80% of caregivers), and recently made a weight loss attempt (58%). While 45% of caregivers believed ALwO would slim down with age, only 24% of HCPs agreed. Most commonly reported weight loss motivators for ALwO were wanting to be more fit/in better shape according to ALwO (40%) and caregivers (32%), and improved confidence/social life according to HCPs (69%). ALwO weight loss barriers included lack of hunger control (most commonly reported by ALwO/caregivers), lack of motivation, unhealthy eating habits (most commonly agreed by HCPs), and lack of exercise.
Conclusions
Misalignment between ALwO, caregivers, and HCPs—including caregivers' underestimation of the impact of obesity on ALwO and HCPs' misperception of key motivators/barriers for weight loss—suggests a need for improved communication and education.
Recombinant human growth hormone (r-hGH) is used as a therapeutic agent for disorders of growth including growth hormone deficiency (GHD) and Turner syndrome (TS). Treatment is costly and current ...methods to model response are inexact. GHD (n = 71) and TS patients (n = 43) were recruited to study response to r-hGH over 5 years. Analysis was performed using 1219 genetic markers and baseline (pre-treatment) blood transcriptome. Random forest was used to determine predictive value of transcriptomic data associated with growth response. No genetic marker passed the stringency criteria for prediction. However, we identified an identical set of genes in both GHD and TS whose expression could be used to classify therapeutic response to r-hGH with a high accuracy (AUC > 0.9). Combining transcriptomic markers with clinical phenotype was shown to significantly reduce predictive error. This work could be translated into a single genomic test linked to a prediction algorithm to improve clinical management. Trial registration numbers: NCT00256126 and NCT00699855.
This is a summary of a research survey called ACTION Teens. In our survey, 12,987 people from 10 countries answered questions about obesity. They were: 5275 teenagers with obesity, 5389 caregivers of ...teenagers with obesity, and 2323 doctors who provide medical care for teenagers with obesity.
Most teenagers with obesity were worried about their weight and thought that losing weight was their responsibility. Many teenagers had already tried to lose weight. For teenagers, wanting to be more fit or in better shape was the top reason for wanting to lose weight. Some caregivers did not realize how worried their teenager was about their own weight. There were also some caregivers who were not aware of their teenager's recent attempts to lose weight. As a group, the doctors did not know the main reasons why teenagers want to lose weight. They also did not know the main reasons preventing teenagers from losing weight.
Teenagers with obesity will be better supported and understood if there is better communication between teenagers, caregivers, and doctors.
: NCT05013359 (ClinicalTrials.gov).
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