Search

Abstract: Cationic antimicrobial peptides play important roles in host defense, linking innate and adaptive immunity. hCAP18, the only human antimicrobial cathelicidin, consists of a conserved N-terminal cathelin-like domain and a C-terminal peptide, LL-37. Expression is regulated during myeloid differentiation, and tightly controlled during infection and inflammation, suggesting active regulation. Using 5′ RACE (rapid amplification of cDNA ends), multiple transcription initiation sites were identified, as well as new splice variants leading to novel augmentations of hCAP18 amino acid composition in bone marrow but not peripheral blood neutrophils. Having expressed hCAP18 promoter constructs in cell lines, we found that full-length (−1739) and truncated (−978) promoter constructs had lower luciferase activities than 5′UTR deletion constructs. Transient transfection of progressively deleted constructs in the non-permissive K562 cell line led us to identify a negative regulatory element within the 53bp immediately upstream of the ATG of hCAP18. Additionally, transient transfection of 5′ deletion constructs identified a positive regulatory element within the 101 bases 5′ of promoter sequence containing two GT-boxes. Negative and positive regulatory elements within the hCAP18 gene promoter provide new insights into the possible molecular basis of myeloid gene expression. [Copyright &y& Elsevier]

Background: Semaphorins and plexins are ligands and cell surface receptors that regulate multiple neurodevelopmental processes such as axonal growth and guidance. PLXNA3 is a plexin gene located on the X chromosome that encodes the most widely expressed plexin receptor in fetal brain, plexin-A3. Plexin-A3 knockout mice demonstrate its role in semaphorin signaling in vivo. The clinical manifestations of semaphorin/plexin neurodevelopmental disorders have been less widely explored. This study describes the neurological and neurodevelopmental phenotypes of boys with maternally inherited hemizygous PLXNA3 variants.Methods: Data-sharing through GeneDx and GeneMatcher allowed identification of individuals with autism or intellectual disabilities (autism/ID) and hemizygous PLXNA3 variants in collaboration with their physicians and genetic counselors, who completed questionnaires about their patients. In silico analyses predicted pathogenicity for each PLXNA3 variant.Results: We assessed 14 boys (mean age, 10.7 [range 2 to 25] years) with maternally inherited hemizygous PLXNA3 variants and autism/ID ranging from mild to severe. Other findings included fine motor dyspraxia (92%), attention-deficit/hyperactivity traits, and aggressive behaviors (63%). Six patients (43%) had seizures. Thirteen boys (93%) with PLXNA3 variants showed novel or very low allele frequencies and probable damaging/disease-causing pathogenicity in one or more predictors. We found a genotype-phenotype correlation between PLXNA3 cytoplasmic domain variants (exons 22 to 32) and more severe neurodevelopmental disorder phenotypes (P < 0.05).Conclusions: We report 14 boys with maternally inherited, hemizygous PLXNA3 variants and a range of neurodevelopmental disorders suggesting a novel X-linked intellectual disability syndrome. Greater understanding of PLXNA3 variant pathogenicity in humans will require additional clinical, computational, and experimental validation. [ABSTRACT FROM AUTHOR]