Risk and prevalence of Relative Energy Deficiency in Sport (REDs) among professional female football players.

A high prevalence of low energy availability (LEA) has been reported in female football players. This is of concern as problematic LEA may evolve into a syndromic pattern known as relative energy deficiency in sport (REDs). Given the difficulties in accurately assessing LEA, our study shifts emphasis to measurable indicators of REDs, serving as proxies for health detriments caused by LEA. The present cross-sectional study aimed to quantify the risk of REDs and to assess the prevalence of indicators indicative of the syndrome. 60 players (tiers 3 and 4) from three Norwegian football teams were analyzed as a single cohort but also stratified based on player position and menstrual status. The proportion of players at risk for REDs was 22%, that is, 17% with mild, 3% with moderate to high, and 2% with very high/extreme risk, respectively. The majority of the cohort (71%) presented with no primary indicators, while 20%, 7%, and 2% presented with one, two, and three primary indicators, respectively. Regarding secondary indicators, 57% had none, 33% had one, and 10% had two indicators. For associated indicators, 30% had none, 42% had one, 18% had two, 8% had three, and 2% had four indicators. Player position did not affect the prevalence of REDs indicators. Among noncontraceptive users (n = 27), secondary amenorrhea (AME) was reported by 30%. These findings indicate that health and performance teams should prioritize universal health promoting strategies rather than selective or indicative strategies. Particularly, focus on nutritional periodization to secure sufficient energy availability, mitigating the risk of problematic LEA and REDs should be addressed.

In Vitro Functional Analysis Can Aid Precision Diagnostics of HNF1B-MODY.

Precision medicine relies on accurate and consistent classification of sequence variants. A correct diagnosis of hepatocyte nuclear factor (HNF) 1B maturity-onset diabetes of the young, caused by pathogenic variants in the HNF1B gene, is important for optimal disease management and prognosis, and it has implications for genetic counseling and follow-up of at-risk family members. We hypothesized that the functional characterization could provide valuable information to assist the interpretation of pathogenicity of HNF1B variants. Using different in vitro functional assays, variants identified among 313 individuals, suspected to have monogenic diabetes with or without kidney disease, were characterized. The data from the functional assays were subsequently conjugated with obtained clinical, biochemical, and in silico data. Two variants (p.A167P, p.H336Pfs∗22) showed severe loss of function due to impaired transactivation, reduced DNA binding (p.A167P), and mRNA instability (p.A167P). Although both these variant carriers were diagnosed with diabetes, the p.H336Pfs∗22 carrier also had congenital absence of a kidney, which is a characteristic trait for HNF1B maturity-onset diabetes of the young. Functional analysis of the p.A167P variant revealed damaging effects on HNF-1B protein function, which may warrant imaging of the kidneys and/or pancreas. In addition, the current study has generated important data, including evidence supporting the benign functional impact of five variants (p.D82N, p.T88A, p.N394D, p.V458G, and p.T544A), and piloting new approaches that will prove critical for the growth of HNF1B-diabetes diagnosis.

Functional characterization of HNF4A gene variants identify promoter and cell line specific transactivation effects.

Hepatocyte nuclear factor-4 alpha (HNF-4A) regulates genes with roles in glucose metabolism and ß-cell development. Although pathogenic HNF4A variants are commonly associated with maturity-onset diabetes of the young (MODY1; HNF4A-MODY), rare phenotypes also include hyperinsulinemic hypoglycemia, renal Fanconi syndrome and liver disease. While the association of rare functionally damaging HNF1A variants with HNF1A-MODY and type 2 diabetes is well established owing to robust functional assays, the impact of HNF4A variants on HNF-4A transactivation in tissues including the liver and kidney is less known, due to lack of similar assays. Our aim was to investigate the functional effects of seven HNF4A variants, located in the HNF-4A DNA binding domain and associated with different clinical phenotypes, by various functional assays and cell lines (transactivation, DNA binding, protein expression, nuclear localization) and in silico protein structure analyses. Variants R85W, S87N and R89W demonstrated reduced DNA binding to the consensus HNF-4A binding elements in the HNF1A promoter (35, 13 and 9%, respectively) and the G6PC promoter (R85W ~10%). While reduced transactivation on the G6PC promoter in HepG2 cells was shown for S87N (33%), R89W (65%) and R136W (35%), increased transactivation by R85W and R85Q was confirmed using several combinations of target promoters and cell lines. R89W showed reduced nuclear levels. In silico analyses supported variant induced structural impact. Our study indicates that cell line specific functional investigations are important to better understand HNF4A-MODY genotype-phenotype correlations, as our data supports ACMG/AMP interpretations of loss-of-function variants and propose assay-specific HNF4A control variants for future functional investigations.