Update on the Kelch-like (KLHL) gene family

Abstract

The Kelch-like (KLHL) gene family encodes a group of proteins that generally possess a BTB/POZ domain, a BACK domain, and five to six Kelch motifs. BTB domains facilitate protein binding and dimerization. The BACK domain has no known function yet is of functional importance since mutations in this domain are associated with disease. Kelch domains form a tertiary structure of β-propellers that have a role in extracellular functions, morphology, and binding to other proteins. Presently, 42 KLHL genes have been classified by the HUGO Gene Nomenclature Committee (HGNC), and they are found across multiple human chromosomes. The KLHL family is conserved throughout evolution. Phylogenetic analysis of KLHL family members suggests that it can be subdivided into three subgroups with KLHL11 as the oldest member and KLHL9 as the youngest. Several KLHL proteins bind to the E3 ligase cullin 3 and are known to be involved in ubiquitination. KLHL genes are responsible for several Mendelian diseases and have been associated with cancer. Further investigation of this family of proteins will likely provide valuable insights into basic biology and human disease.

Further Evidence for the Implication of LZTR1, a Gene not Associated with the Ras-Mapk Pathway, in the Pathogenesis of Noonan Syndrome

“…The clinical findings of NS patients with LZTR1 variants were similar to PTPN11 positive individuals with the exception of short stature which was not frequent in the Brazilian cohort [19]. Our patient, contrary to what has been reported, had a short stature at -4,3 SD (Standard Deviation).…”

“…All the reported LZTR1 variants are localized in highly conserved kelch (KT) domain and are predicted to disrupt protein function. Kelch domain shape may also be responsible for binding to other proteins [19,20]. The missense heterozygous variant found in LZTR1 in our patient is localized in KT1 domain.…”

Characterizations of Three Major Cysteine Sensors of Keap1 in Stress Response

“…Keap1 is a member of the Kelch-like (KLHL) family that generally possesses BTB and Kelch domains. KLHL family members have a potential to form a Cul3-based ubiquitin ligase complex (32). Alignment of human KLHL family revealed that the cysteine residues at the positions of Cys273 and Cys288 are conserved in various mammalians but not in the other KLHL family proteins (Fig.…”

Duplication of PTHLH causes osteochondroplasia with a combined brachydactyly type E/A1 phenotype with disturbed bone maturation and rhizomelia

“…15 Other members like the kelch-like (KLHL) gene family have been shown to be involved in renal Na+ and Cl − homeostasis. 16 It is also possible that the different duplications have effects on long-range regulation of PTHLH and thereby result in variable PTHLH expression levels causing the phenotypic differences. The differential effects of PTHLH in the hands and carpals of the patients remain difficult to explain.…”