The third human FER-1-like protein is highly similar to dysferlin

Dysferlin, the protein product of the gene mutated in patients with an auto somal recessive limb-girdle muscular dystrophy type 2B (LGMDBB) and a dista l muscular dystrophy, Miyoshi myopathy, is homologous to a Caenorhabditis e legans spermatogenesis factor, FER-1. Analysis of fer-1 mutants and of sequ ence predictions of the FER-1 and dysferlin ORFs has predicted a role in me mbrane fusion. Otoferlin, another human FER-1-like protein (ferlin), has re cently been Shown to be responsible for autosomal recessive nonsyndromic de afness (DFNB9). In this report we describe the third human ferlin gene, FER 1L3 which maps to chromosome 10q23.3. Expression analysis of the orthologou s mouse gene shows ubiquitous expression but predominant expression in the eye, esophagus, and salivary gland. All the ferlins are characterized by se quences corresponding to multiple C2 domains that share the highest level o f homology with the C2A domain of rat synaptotagmin III. They are predicted to be Type II transmembrane proteins, with the majority of the protein fac ing the cytoplasm anchored by the C-terminal transmembrane domain. Sequence and predicted structural comparisons have highlighted the high degree of s imilarity of dysferlin and FER1L3, which have sequences corresponding to si x C2 domains and which share more than 60% amino acid sequence identity. (C ) 2000 Academic Press.