Background:Spinal muscular atrophy (SMA) is the most common inherited lethal disease of children. Various genetic deletions involving the bi-allelic loss of SMN1 exon 7 are reported to account for 94% of affected individuals. Published literature places the carrier frequency for SMN1 mutations between 1 in 25 and 1 in 50 in the general population. Although SMA is considered to be a pan-ethnic disease, carrier frequencies for many ethnicities, including most ethnic groups in North America, are unknown.Objectives and methods:To provide an accurate assessment of SMN1 mutation carrier frequencies in African American, Ashkenazi Jewish, Asian, Caucasian, and Hispanic populations, more than 1000 specimens in each ethnic group were tested using a clinically validated, quantitative real-time polymerase chain reaction (PCR) assay that measures exon 7 copy number.Results:The observed one-copy genotype frequency was 1 in 37 (2.7%) in Caucasian, 1 in 46 (2.2%) in Ashkenazi Jew, 1 in 56 (1.8%) in Asian, 1 in 91 (1.1%) in African American, and 1 in 125 (0.8%) in Hispanic specimens. Additionally, an unusually high frequency of alleles with multiple copies of SMN1 was identified in the African American group (27% compared to 3.3–8.1%). This latter finding has clinical implications for providing accurate adjusted genetic risk assessments to the African American population.Conclusions:Differences in the frequency of SMA carriers were significant among several ethnic groups. This study provides an accurate assessment of allele frequencies and estimates of adjusted genetic risk that were previously unavailable to clinicians and patients considering testing.

A nimal growth and development rely on coordinated functions of body organs to balance energy consumption and storage under optimal or challenging conditions, such as food scarcity or pathogen attack. When adverse conditions are temporary, animals survive by lengthening development and postponing maturity, reducing their body size (16,65). In contrast, prolonged starvation or chronic inflammation may exhaust energy reserves, causing death (32, 69). The key nutrient-sensing, metabolic, and immune-signaling pathways are functionally conserved across phyla. In the fruit fly Drosophila melanogaster, as in vertebrates, insulin/insulin growth factor (IGF) signaling (IIS) primarily regulates growth and metabolic homeostasis (56). The innate immune response of the fly relies on the Toll receptor and the immune deficiency (Imd) pathways (35). In response to bacterial or fungal infection, the Toll and Imd pathways engage downstream transcription factors of the NF-B-like family (Dif, Dorsal, and Relish) that in turn trigger synthesis of a battery of antimicrobial peptides (AMPs).It has become evident that the metabolic and immune system responses are tightly interconnected. Selective activation of Toll signaling in the Drosophila fat body attenuates IIS to reduce nutrient stores and overall growth (14). Mycobacterial infection causes energy wasting due to the systemic activation of the Forkhead transcription factor FOXO (15). Activation of the Jun N-terminal kinase (JNK) pathway is a well-established example of antagonistic regulation of IIS in both flies and vertebrates (29). Chronic inflammation, accompanied by high JNK activity, is at the heart of the metabolic syndrome and type 2 diabetes (54). Interestingly, genetic removal of IIS pathway components, starvation, and DNA damage all induce AMP expression in the absence of infection. This infection-independent AMP upregulation requires both FOXO (5) and Relish (30,70), further supporting the notion that maintenance of metabolic and innate immune balance are intimately linked.The Drosophila fat body and gut integrate metabolic and inflammatory signals to coordinate energy use. The fly alimentary tract digests and absorbs nutrients, while the fat body metabolizes and stores them. In addition, both organs can mount an immune response. The fat body requires both the Toll and Imd pathways for AMP production, whereas the gut immune response relies solely on Imd signaling (35,62). In contrast to the low basal immune activity within the unchallenged fat body, the presence of commensal bacteria in the gut lumen keeps the gut epithelium permanently alert with activated nuclear Relish. In this case, additional factors, such as the homeobox gene caudal (49), control AMP expression. Tightly regulated production of positive and negative Imd modulators prevents overgrowth of pathogens while preserving beneficial commensal bacteria. Uncontrolled inflammatory response of the intestinal epithelium has a dramatic impact on gut physiology and homeostasis in both flies and humans (43,47). A ...

Summary Homeostatic renewal and stress-related tissue regeneration rely on stem cell activity, which drives the replacement of damaged cells to maintain tissue integrity and function. The Jun N-terminal kinase (JNK) signaling pathway has been established as a critical regulator of tissue homeostasis both in intestinal stem cells (ISCs) and mature enterocytes (ECs), while its chronic activation has been linked to tissue degeneration and aging. Here, we show that JNK signaling requires the stress-inducible transcription factor Ets21c to promote tissue renewal in Drosophila . We demonstrate that Ets21c controls ISC proliferation as well as EC apoptosis through distinct sets of target genes that orchestrate cellular behaviors via intrinsic and non-autonomous signaling mechanisms. While its loss appears dispensable for development and prevents epithelial aging, ISCs and ECs demand Ets21c function to mount cellular responses to oxidative stress. Ets21c thus emerges as a vital regulator of proliferative homeostasis in the midgut and a determinant of the adult healthspan.