FLNA-filaminopathy skeletal phenotypes are not due to an osteoblast autonomous loss-of-function.

Mutations in FLNA, which encodes the cytoskeletal protein FLNA, cause a spectrum of sclerosing skeletal dysplasias. Although many of these genetic variants are recurrent and cluster within the gene, the pathogenic mechanism that underpins the development of these skeletal phenotypes is unknown. To determine if the skeletal dysplasia in FLNA-related conditions is due to a cell-autonomous loss-of-function localising to osteoblasts and/or osteocytes, we utilised mouse models to conditionally remove Flna from this cellular lineage. Flna was conditionally knocked out from mature osteocytes using the Dmp1-promoter driven Cre-recombinase expressing mouse, as well as the committed osteoblast lineage using the Osx-Cre or Col1a1-Cre expressing lines. We measured skeletal parameters with µCT and histological methods, as well as gene expression in the mineralised skeleton. We found no measureable differences between the conditional Flna knockout mice, and their control littermate counterparts. Moreover, all of the conditional Flna knockout mice, developed and aged normally. From this we concluded that the skeletal dysplasia phenotype associated with pathogenic variants in FLNA is not caused by a cell-autonomous loss-of-function in the osteoblast-osteocyte lineage, adding more evidence to the hypothesis that these phenotypes are due to gain-of-function in FLNA.

Kidney-Function Trajectories From Young Adulthood to Midlife: Identifying Risk Strata and Opportunities for Intervention.

Introduction: Understanding normative patterns of change in kidney function over the life course may allow targeting of early interventions to slow or prevent the onset of kidney disease, but knowledge about kidney functional change before middle age is limited. This study used prospective longitudinal data from a representative birth cohort to examine common patterns of change from young to midadulthood and to identify risk factors and outcomes associated with poorer trajectories. Methods: We used group-based trajectory modeling in the Dunedin study birth cohort (n = 857) to identify the following: (i) common kidney function trajectories between the ages 32 and 45 years, (ii) early-life factors associated with those trajectories, (iii) modifiable physical and psychosocial factors across adulthood associated with differences in trajectory slope, and (iv) links between trajectories and kidney-related outcomes at age 45 years. Results: Three trajectory groups were identified and could be differentiated by age 32 years as follows: normal (58% of participants), low-normal (36%), and high-risk (6%) groups. Those from low socioeconomic backgrounds had higher odds of following a high-risk (vs. normal) trajectory. Modifiable factors (blood pressure, body mass index, inflammation, glycated hemoglobin, smoking, and socioeconomic status) across adulthood were associated with steeper age-related declines in kidney function, particularly among those in the low-normal and high-risk groups. Those in the low-normal and high-risk groups also had more adverse kidney-related outcomes at age 45 years. Conclusion: The current findings could be used to inform the development of early interventions and point to socioeconomic conditions across the life course and health-related risk factors and behaviors in adulthood as kidney health promotion targets.