Alternative titles; symbols
HGNC Approved Gene Symbol: FLII
Cytogenetic location: 17p11.2 Genomic coordinates (GRCh38): 17:18,244,815-18,259,022 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p11.2 | Cardiomyopathy, dilated, 2J | 620635 | Autosomal recessive | 3 |
FLII is critically involved in cell adhesion dynamics and associated cytoskeletal rearrangements, with an important role in cardiomyocyte cell adhesion and myofibril organization by regulating adhesion complex localization at an interface between myofibrils and their attachment to cardiomyocyte cell adhesion complexes (summary by Ruijmbeek et al., 2023).
Campbell et al. (1993) cloned and characterized cDNAs for the Drosophila melanogaster flightless I gene (FliI) and of homologous cDNAs from Caenorhabditis elegans and from humans. The amino acid sequence deduced from the FLI cDNA has 52% similarity to that of the human gelsolin (137350) protein and also has an N-terminal leucine-rich domain with 16 consecutive leucine-rich repeats. Campbell et al. (1997) stated that the FLII gene encodes a predicted 1,269-amino acid protein. Northern blot analysis revealed FLII expression as an approximately 4.4-kb mRNA in all tissues tested, with strongest expression in skeletal muscle.
In zebrafish, Ruijmbeek et al. (2023) observed flii expression throughout all stages of embryonic development. Single-cell RNA sequencing data from human and zebrafish cardiac tissue revealed uniform and widespread distribution of FLII expression. In adult zebrafish myocardial tissue, Flii was present in ventricular cardiomyocytes, where it localized to cardiomyocyte cell-cell adhesion structures (intercalated discs) and to cardiomyocyte cell-matrix adhesions (costamere-like structures).
Campbell et al. (1997) stated that the FLII gene contains 30 exons and spans 14 kb. In both mouse and human, the FLII gene is adjacent to LLGL1 (600966), and the 3-prime ends of the 2 transcripts overlap. The overlap region contains poly(A) signals for both genes and is highly conserved between human and mouse.
Chen et al. (1995) demonstrated that the human FLI homolog maps within the microdeletion critical region defined for Smith-Magenis syndrome (SMS; 182290) on chromosome 17p11.2. This was the first gene mapped to the deleted region. Campbell et al. (2002) noted that the mouse Flii gene maps to a region of chromosome 11 with syntenic homology to a portion of the SMS critical region.
By Southern blot analysis of somatic cell hybrids and/or fluorescence in situ hybridization analysis of lymphoblastoid cell lines from 12 unrelated SMS patients, Chen et al. (1995) demonstrated the deletion of 1 copy of FLI in all.
In 2 unrelated Saudi children with dilated cardiomyopathy (CMD2J; 620635), Al-Hassnan et al. (2020) identified homozygosity for missense mutations in the FLII gene: an R1240C substitution (600362.0001) in the affected 7-year-old boy from the first family, and an L674V substitution (600362.0002) in the affected 3-year-old girl from the second family. Their unaffected consanguineous parents were heterozygous for the mutations, which were both present at low minor allele frequency (MAF for each, 0.0008) in the Saudi Human Genome Project database; the L674V substitution was not found in the gnomAD database, whereas the R1240C variant was present at very low MAF (0.00005).
In a 2-year-old Dutch girl with early-onset CMD, Ruijmbeek et al. (2023) identified compound heterozygosity for a nonsense mutation (Q454X; 600362.0003) and a missense mutation (R1168W; 600362.0004) in the FLII gene. Sanger sequencing confirmed the mutations and their segregation with disease in the family. The nonsense mutation was not found in the gnomAD database, whereas the missense mutation was present at very low MAF (0.000024). Analysis of corresponding flii mutations in zebrafish suggested that patient-specific alleles are hypomorphic and cause early-onset CMD through reduced FLII activity.
Campbell et al. (2002) constructed a transgenic mouse carrying the complete human FLII gene. FLII rescued Flii -/- mice from early, pregastrulation, embryonic death and restored normal development to these mice.
Using CRISPR/Cas9 genome editing in zebrafish, Ruijmbeek et al. (2023) introduced nucleotide modifications mimicking human CMD-associated variants. Larvae with patient-specific mutations displayed significantly reduced ventricular contractility, as indicated by a decreased fractional area change. Larvae homozygous for flii R1230C, corresponding to FLII R1240C (600362.0001), showed less organized and more primitive myocardial trabeculae. The authors also studied a previously published zebrafish line, homozygous for a premature stop codon in exon 5, thus lacking substantial parts of the Flii protein including functional gelsolin domains. During ventricular chamber morphogenesis, Flii deficiency resulted in prominent structural defects in cardiomyocytes, affecting cell adhesion and myofibrillar architecture, as well as causing severe trabeculation defects at the cellular level. In addition, Flii function was shown to be essential for the activation of 2 signaling pathways, Notch (see 190198) and Hippo (see 605030), known to be involved in ventricular chamber morphogenesis. The defects culminated in severely compromised cardiac wall morphogenesis, systolic heart failure, and larval death. In comparison with the stop-codon mutants, zebrafish with patient-specific variants exhibited a more subtle phenotype, with distinctive myofibrillar disorganization and concomitantly reduced ventricular contractility, and were able to survive past the larval stage. The authors concluded that these patient-specific alleles are hypomorphic and cause early-onset CMD through reduced FLII activity.
In a 7-year-old Saudi boy (family D-071) with dilated cardiomyopathy (CMD2J; 620635), Al-Hassnan et al. (2020) identified homozygosity for a c.3718C-T transition (c.3718C-T, GRCh37) in the FLII gene, resulting in an arg1240-to-cys (R1240C) substitution at a highly conserved residue. His unaffected consanguineous parents and an unaffected brother were heterozygous for the mutation, which was present at low minor allele frequencies in the Saudi Human Genome Project (0.0008) and gnomAD (0.00005) databases.
Ruijmbeek et al. (2023) noted that the c.3718C-T transition in exon 30 of the FLII gene resulted in an R1240C substitution at an evolutionarily conserved residue. They stated that neither parent in family D-071 showed clinical signs of CMD on cardiac screening. Zebrafish homozygous for the corresponding flii R1230C variant exhibited less organized and more primitive myocardial trabecula, with concomitantly reduced ventricular contractility.
In a 3-year-old Saudi girl (family D-151) with dilated cardiomyopathy (CMD2J; 620635), Al-Hassnan et al. (2020) identified homozygosity for a c.2020C-G transversion (c.2020C-G, GRCh37) in the FLII gene, resulting in a leu674-to-val (L274V) substitution. Her unaffected parents were heterozygous for the substitution, which was not found in the gnomAD database but was present at low minor allele frequency (0.0008) in the Saudi Human Genome Project database.
Ruijmbeek et al. (2023) noted that the c.2020C-G transversion in exon 18 of the FLII gene resulted in an L674V substitution at an evolutionarily conserved residue. They stated that neither parent in family D-151 showed clinical signs of CMD on cardiac screening.
In a 2-year-old Dutch girl with dilated cardiomyopathy (CMD2J; 620635), Ruijmbeek et al. (2023) identified compound heterozygosity for mutations in the FLII gene: a c.1360C-T transition (c.1360C-T, GRCh37) in exon 12, resulting in a gln454-to-ter (Q454X) substitution, and a c.3502C-T transition in exon 27, resulting in an arg1169-to-trp (R1168W; 600362.0004) substitution at a highly conserved residue. Her unaffected parents, unaffected twin brother, and unaffected sister were each heterozygous for 1 of the mutations. The nonsense mutation was not found in the gnomAD database, whereas the missense mutation was present at very low MAF (0.000024).
For discussion of the c.3502C-T transition (c.3502C-T, GRCh37) in exon 27 of the FLII gene, resulting in an arg1160-to-trp (R1168W) substitution, that was found in compound heterozygous state in a 2-year-old Dutch girl with dilated cardiomyopathy (CMD2J; 620635) by Ruijmbeek et al. (2023), see 600362.0003.
Al-Hassnan, Z. N., Almesned, A., Tulbah, S., Alakhfash, A., Alhadeq, F., Alruwaili, N., Alkorashy, M., Alhashem, A., Alrashdan, A., Faqeih, E., Alkhalifi, S. M., Al Humaidi, Z., and 22 others. Categorized genetic analysis in childhood-onset cardiomyopathy. Circ. Genom. Precis. Med. 13: 504-514, 2020. [PubMed: 32870709] [Full Text: https://doi.org/10.1161/CIRCGEN.120.002969]
Campbell, H. D., Fountain, S., McLennan, I. S., Berven, L. A., Crouch, M. F., Davy, D. A., Hooper, J. A., Waterford, K., Chen, K.-S., Lupski, J. R., Ledermann, B., Young, I. G., Matthaei, K. I. Fliih, a gelsolin-related cytoskeletal regulator essential for early mammalian embryonic development. Molec. Cell. Biol. 22: 3518-3526, 2002. [PubMed: 11971982] [Full Text: https://doi.org/10.1128/MCB.22.10.3518-3526.2002]
Campbell, H. D., Fountain, S., Young, I. G., Claudianos, C., Hoheisel, J. D., Chen, K.-S., Lupski, J. R. Genomic structure, evolution, and expression of human FLII, a gelsolin and leucine-rich-repeat family member: overlap with LLGL. Genomics 42: 46-54, 1997. [PubMed: 9177775] [Full Text: https://doi.org/10.1006/geno.1997.4709]
Campbell, H. D., Schimansky, T., Claudianos, C., Ozsarac, N., Kasprzak, A. B., Cotsell, J. N., Young, I. G., de Couet, H. G., Gabor Miklos, G. L. The Drosophila melanogaster flightless-I gene involved in gastrulation and muscle degeneration encodes gelsolin-like and leucine-rich repeat domains and is conserved in Caenorhabditis elegans and humans. Proc. Nat. Acad. Sci. 90: 11386-11390, 1993. [PubMed: 8248259] [Full Text: https://doi.org/10.1073/pnas.90.23.11386]
Chen, K.-S., Gunaratne, P. H., Hoheisel, J. D., Young, I. G., Gabor Miklos, G. L., Greenberg, F., Shaffer, L. G., Campbell, H. D., Lupski, J. R. The human homologue of the Drosophila melanogaster flightless-I gene (flil) maps within the Smith-Magenis microdeletion critical region in 17p11.2. Am. J. Hum. Genet. 56: 175-182, 1995. [PubMed: 7825574]
Ruijmbeek, C. W. B., Housley, F., Idrees, H., Housley, M. P., Pestel, J., Keller, L., Lai, J. K. H., van der Linde, H. C., Willemsen, R., Piesker, J., Al-Hassnan, Z. N., Almesned, A., and 9 others. Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization. JCI Insight 8: e168247, 2023. [PubMed: 37561591] [Full Text: https://doi.org/10.1172/jci.insight.168247]