Alternative titles; symbols
HGNC Approved Gene Symbol: LHFPL5
Cytogenetic location: 6p21.31 Genomic coordinates (GRCh38) : 6:35,805,352-35,824,070 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.31 | Deafness, autosomal recessive 67 | 610265 | Autosomal recessive | 3 |
The spontaneous hurry-scurry (hscy) mutation in mice causes deafness and vestibular dysfunction. Longo-Guess et al. (2005) positionally cloned the gene mutated in hscy mice, Lhfpl5, which they called Tmhs. The deduced 216-amino acid protein contains 4 transmembrane domains. Northern blot analysis of several adult mouse tissues detected Tmhs only in brain. Immunofluorescent localization showed no significant Tmhs in brain sections, but there was intense fluorescence in the inner ear, particularly on stereocilia of both inner and outer hair cells.
Longo-Guess et al. (2005) determined that the mouse Lhfpl5 gene contains 4 exons and spans 7.9 kb.
Longo-Guess et al. (2005) mapped the mouse Lhfpl5 gene to a region of chromosome 17 that shows homology of synteny to human chromosome 6p21.31.
In a Pakistani family with autosomal recessive nonsyndromic hearing loss that mapped to 6p22.3 and was designated DFNB67 (610265), Shabbir et al. (2006) identified a 246delC mutation in the LHFPL5 gene predicted to cause a truncation of the protein at residue 84 (609427.0001). In 2 large Turkish consanguineous families, Kalay et al. (2006) found a homozygous 1-bp deletion (609427.0003) and a missense mutation (609427.0004), respectively, in the LHFPL5 gene. Mutation screening of the homologous LHFPL3 (609719) and LHFPL4 (610240) genes did not reveal any disease-causing mutation. The findings suggested that LHFPL5 is essential for normal function of the human cochlea.
In 12 children from 9 families on Reunion Island with congenital deafness and vestibular dysfunction, Lerat et al. (2019) identified homozygous or compound heterozygous mutations in the LHFPL5 gene: a 1-bp deletion (c.185delT; 609427.0005) and a missense mutation (R158W; 609427.0006). The variants segregated with disease in the families, and genotype analysis revealed c.185delT to be a founder mutation.
Longo-Guess et al. (2005) stated that the overt phenotype of hscy mice consists of circling behavior, frequent head shaking for side to side, and an inability to swim. Mutant mice also show no response to auditory stimuli. By examining cochlear cross-sections, Longo-Guess et al. (2005) found that hscy mice have severe degeneration of the organ of Corti. They identified a G-to-T transversion at nucleotide 482 of the Tmhs gene, resulting in a cys161-to-phe substitution, as the cause of the hscy phenotype.
Longo-Guess et al. (2005) found that deafness and vestibular function in the 'hurry-scurry' (hscy) mouse is associated with a homozygous cys161-to-phe mutation in the Lhfpl5 gene.
In a consanguineous Pakistani family, Shabbir et al. (2006) found that nonsyndromic hearing loss mapping to 6p21.3 (DFNB67; 610265) was associated with a homozygous deletion in the LHFPL5 gene, 246delC, leading to an unchanged pro83 followed by a stop codon (Pro83ProfsTer1). Even if the mRNA was not decayed, the truncated protein would lack 3 of its 4 transmembrane domains and thus would most likely show loss of function.
In a consanguineous Pakistani family, Shabbir et al. (2006) found that autosomal recessive nonsyndromic hearing loss (DFNB67; 610265) was associated with homozygosity for a missense mutation in the LHFPL5 gene: tyr127 to cys (Y127C).
In a large Turkish consanguineous family, Kalay et al. (2006) found that autosomal recessive nonsyndromic hearing loss (DFNB67; 610265) was associated with homozygosity for a 1-bp deletion in exon 2 of the LHFPL5 gene: 649delG (Glu216ArgfsTer26). Further screening of index patients from 96 Turkish autosomal recessive nonsyndromic hearing loss families and 90 Dutch patients identified 1 additional Turkish patient carrying the 649delG mutation. Haplotype analysis revealed that the mutation was present on the same haplotype in both families.
In a consanguineous Turkish family, Kalay et al. (2006) found that autosomal recessive nonsyndromic hearing loss (DFNB67; 610265) was associated with a 494C-T transition in exon 2 of the LHFPL5 gene that caused a thr165-to-met substitution (T165M).
In 7 unrelated children from Reunion Island with congenital profound deafness and vestibular dysfunction (DNFB67; 610265), Lerat et al. (2019) identified homozygosity for a 1-bp deletion (c.185delT) in the LHFPL5 gene, causing a frameshift predicted to result in a premature termination codon (Phe62SerfsTer23). In 5 children from 2 additional families on Reunion Island (families 1 and 2) with deafness and vestibular dysfunction, they identified compound heterozygosity for c.185delT and a c.472C-T transition in LHFPL5, resulting in an arg158-to-trp (R158W; 609427.0006) substitution. The variants segregated with disease in the families. Genotype analysis revealed c.185delT to be a founder mutation; the authors identified the ancestor couple common to all 9 families as Alexis and Brigitte, born in 1693 on Reunion Island, but whose parents arrived from mainland France on 2 different boats, in 1665 and 1674.
For discussion of the c.472C-T transition in the LHFPL5 gene, resulting in an arg158-to-trp (R158W) substitution, that was found in compound heterozygous state in 5 children from 2 families from Reunion Island (families 1 and 2) with profound congenital deafness and vestibular dysfunction (DFNB67; 610265) by Lerat et al. (2019), see 609427.0005.
The R158W variant had previously been reported by Komara et al. (2016) in homozygosity in a Yemeni girl with bilateral profound sensorineural hearing loss who also had cerebellar ataxia-2 (CAMRQ2; 610185) and homozygous mutation in the WDR81 gene (614218.0002).
Kalay, E., Li, Y., Uzumcu, A., Uyguner, O., Collin, R. W., Caylan, R., Ulubil-Emiroglu, M., Kersten, F. F. J., Hafiz, G., van Wijk, E., Kayserili, H., Rohmann, E., and 16 others. Mutations in the lipoma HMGIC fusion partner-like 5 (LHFPL5) gene cause autosomal recessive nonsyndromic hearing loss. Hum. Mutat. 27: 633-639, 2006. [PubMed: 16752389] [Full Text: https://doi.org/10.1002/humu.20368]
Komara, M., John, A., Suleiman, J., Ali, B. R., Al-Gazali, L. Clinical and molecular delineation of dysequilibrium syndrome type 2 and profound sensorineural hearing loss in an inbred Arab family. Am. J. Med. Genet. 170A: 540-543, 2016. [PubMed: 26437881] [Full Text: https://doi.org/10.1002/ajmg.a.37421]
Lerat, J., Bonnet, C., Cartault, F., Loundon, N., Jacquemont, M. L., Darcel, F., Rouillon, I., Mezouaghi, K., Guichet, A., Litzler, J., Gesny, R., Gherbi, S., Aissa, I. B., Digeon, F. S. J., Garabedian, E. N., Bonnefont, J. P., Genin, E., Denoyelle, F., Jonard, L., Marlin, S. High prevalence of congenital deafness on Reunion Island is due to a founder variant of LHFPL5. Clin. Genet. 95: 177-181, 2019. [PubMed: 30298622] [Full Text: https://doi.org/10.1111/cge.13460]
Longo-Guess, C. M., Gagnon, L. H., Cook, S. A., Wu, J., Zheng, Q. Y., Johnson, K. R. A missense mutation in the previously undescribed gene Tmhs underlies deafness in hurry-scurry (hscy) mice. Proc. Nat. Acad. Sci. 102: 7894-7899, 2005. [PubMed: 15905332] [Full Text: https://doi.org/10.1073/pnas.0500760102]
Shabbir, M. I., Ahmed, Z. M., Khan, S. Y., Riazuddin, S., Waryah, A. M., Khan, S. N., Camps, R. D., Ghosh, M., Kabra, M., Belyantseva, I. A., Friedman, T. B., Riazuddin, S. Mutations of human TMHS cause recessively inherited nonsyndromic hearing loss. J. Med. Genet. 43: 634-640, 2006. [PubMed: 16459341] [Full Text: https://doi.org/10.1136/jmg.2005.039834]