Alternative titles; symbols
HGNC Approved Gene Symbol: KLHL41
Cytogenetic location: 2q31.1 Genomic coordinates (GRCh38) : 2:169,509,702-169,526,258 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q31.1 | Nemaline myopathy 9 | 615731 | Autosomal recessive | 3 |
The KLHL41 gene encodes a protein that plays a role in skeletal muscle differentiation (summary by Gupta et al., 2013).
By characterizing cDNA clones showing high abundance in an adult skeletal muscle cDNA library, Garrison et al. (1985) identified a partial sarcosin cDNA, which they designated clone P2a. Using this clone as probe, Taylor et al. (1998) identified 2 related sarcosin transcripts in a second adult skeletal muscle cDNA library. The longer transcript contained a 3-prime extension due to use of a second polyadenylation signal. Both transcripts encode a deduced 435-amino acid protein with a calculated molecular mass of about 48.5 kD. Northern blot analysis detected transcripts at 2.3 kb and 2.7 kb in heart and skeletal muscle and not in other tissues. Minor expression was also found in smooth muscle from prostate. Densitometry revealed that the longer transcript represented 57% of the expressed mRNA.
Stumpf (2025) mapped the KLHL41 gene to chromosome 2q31.1 based on an alignment of the KLHL41 sequence (GenBank AF333387) with the genomic sequence (GRCh38).
Gupta et al. (2013) found expression of the KLHL41 gene over the I-bands of the sarcomere and at perinuclear regions in human skeletal muscle biopsies and cultured murine myofibers. There was KLHL41 immunostaining around the sarcoplasmic reticulum/endoplasmic reticulum membranes. Klhl41 was detected in mouse diaphragm and skeletal muscle, and levels of the protein increased during differentiation to myotubes.
In 5 unrelated children with nemaline myopathy-9 (NEM9; 615731), Gupta et al. (2013) identified homozygous or compound heterozygous mutations in the KLHL41 gene (see, e.g., 607701.0001-607701.0005). The mutations in 4 patients were found by homozygosity mapping combined with whole-exome sequencing; the fifth patient was identified from a cohort of 116 patients who underwent Sanger sequencing of the KLHL41 gene. There was a clear genotype-phenotype correlation, with truncating mutations resulting in severe phenotypes with neonatal death, and missense changes resulting in impaired motor function with survival into late childhood and/or early adulthood. Immunoblotting of patient skeletal muscle showed decreased levels of KLHL41 compared to wildtype. Functional studies in zebrafish showed that loss of klhl41 resulted in highly diminished motor function and myofibrillar disorganization with nemaline body formation.
Gupta et al. (2013) studied the 2 duplicated zebrafish orthologs (klhl41a/klhl41b) of KLHL41. Whole-mount in situ hybridization showed ubiquitous expression of klhl41a at 1 day postfertilization (dpf), but by 2 dpf, klhl41a expression was virtually absent in major axial skeletal muscles. In contrast, klhl41b expression was predominantly seen in striated muscles, and strong expression in heart and skeletal muscles was observed throughout development to at least 5 dpf. Knockdown of Klhl41 orthologs in zebrafish embryos resulted in a higher incidence of disorganized skeletal muscle structure, pericardial edema, curved bodies, muscle weakness, and lethality compared to wildtype. Electron microscopy of mutant zebrafish muscle showed myofibrillar disorganization with Z-line thickening and electron-dense structures, reminiscent of nemaline bodies. These findings suggested a role for KLHL41 in skeletal muscle development and maintenance.
In a boy of Russian origin with nemaline myopathy-9 (NEM9; 615731), Gupta et al. (2013) identified a homozygous 1-bp deletion and 4-bp insertion in exon 1 of the KLHL41 gene (c.459delinsACTC), resulting in a single amino acid insertion (Ser153_Ala154insLeu). The mutation was found by whole-exome sequencing, but segregation in the family could not be determined because the child was adopted. The variant was present at a less than 3% frequency in the dbSNP (build 135), 1000 Genomes Project, and Exome Variant Server databases. The patient had a congenital form of the disorder with distal weakness greater than proximal weakness, but was ambulant at age 12 years.
In an Afghan boy, born of consanguineous parents, with severe nemaline myopathy-9 (NEM9; 615731), Gupta et al. (2013) identified a homozygous 8-bp deletion (c.1748_1755delAAGGAAAT) in exon 6 of the KLHL41 gene, resulting in a frameshift and premature termination (Lys583ThrfsTer7). The mutation, which was found by whole-exome sequencing combined with homozygosity mapping and confirmed by Sanger sequencing, segregated with the disorder in the family. The child was born with fetal akinesia sequence and no antigravity movements at birth; he died at age 3 months.
In a Saudi Arabian infant, born of consanguineous parents, with severe nemaline myopathy-9 (NEM9; 615731), Gupta et al. (2013) identified a homozygous 1-bp deletion (c.641delA) in exon 1 of the KLHL41 gene, resulting in a frameshift and premature termination (Asn214ThrfsTer14). The mutation, which was found by whole-exome sequencing and autozygosity mapping, was not found in 240 control Saudi exomes and in less than 3% of the dbSNP (build 135) database. The child was born with fetal akinesia sequence and weak fetal movements; he died on the first day of life.
In a boy of Chinese descent with nemaline myopathy-9 (NEM9; 615731), Gupta et al. (2013) identified compound heterozygous mutations in the KLHL41 gene: a 3-bp deletion (c.581_583delAAG) in exon 1, resulting in the deletion of residue glu194, and a c.1238C-T transition in exon 2, resulting in a ser413-to-leu (S413L; 607701.0005) substitution at a conserved residue. The patient was 1 of 116 individuals who underwent direct sequencing of the KLHL41 gene. The patient was ambulant at age 5 years.
For discussion of the ser413-to-leu (S413L) mutation in the KLHL41 gene that was found in compound heterozygous state in a patient with nemaline myopathy-9 (NEM9; 615731) by Gupta et al. (2013), see 607701.0004.
Garrison, J. C., Hardeman, E., Wade, R., Kedes, L., Gunning, P. Isolation of full-length cDNAs encoding abundant adult human skeletal muscle mRNAs. Gene 38: 177-188, 1985. [PubMed: 3840762] [Full Text: https://doi.org/10.1016/0378-1119(85)90216-1]
Gupta, V. A., Ravenscroft, G., Shaheen, R., Todd, E. J., Swanson, L. C., Shiina, M., Ogata, K., Hsu, C., Clarke, N. F., Darras, B. T., Farrar, M. A., Hashem, A., and 18 others. Identification of KLHL41 mutations implicates BTB-kelch-mediated ubiquitination as an alternate pathway to myofibrillar disruption in nemaline myopathy. Am. J. Hum. Genet. 93: 1108-1117, 2013. [PubMed: 24268659] [Full Text: https://doi.org/10.1016/j.ajhg.2013.10.020]
Stumpf, A. M. Personal Communication. Baltimore, Md. 2/25/2025.
Taylor, A., Obholz, K., Linden, G., Sadiev, S., Klaus, S., Carlson, K. D. DNA sequence and muscle-specific expression of human sarcosin transcripts. Molec. Cell. Biochem. 183: 105-112, 1998. [PubMed: 9655184] [Full Text: https://doi.org/10.1023/a:1006824331819]