#601412
Table of Contents
A number sign (#) is used with this entry because of evidence that autosomal dominant deafness-7 (DFNA7) is caused by heterozygous mutation in the LMX1A gene (600298) on chromosome 1q22.
Autosomal dominant deafness-7 (DFNA7) is a form of progressive sensorineural hearing loss with highly variable age at onset and severity, even within families. The age at onset ranges from congenital to mid-adulthood. Some patients may have associated vertigo (summary by Wesdorp et al., 2018).
Fagerheim et al. (1996) described a large Norwegian family with autosomal dominant nonsyndromic progressive high-tone hearing loss. In the majority of affected family members examined with successive audiograms, the hearing loss was greater than 45 dB by age 15 years. Linkage analysis was performed in this family (see MAPPING), but additional genetic and DNA studies were not performed.
Wesdorp et al. (2018) reported 2 large unrelated families of Dutch origin in which 7 individuals had autosomal dominant nonsyndromic sensorineural hearing loss. The age at onset and the phenotype were highly variable, even within families. Two unrelated patients had onset at birth, 1 had childhood onset, 1 had onset at puberty, and 3 had onset between 26 and 35 years of age. The hearing loss, which was progressive for most patients, was mild to profound and associated with a downward sloping audiogram. Four patients had vestibular involvement with evidence of hyporeflexia manifest as vertigo and tinnitus; oculomotor testing was normal.
The transmission pattern of DFNA7 in the families reported by Wesdorp et al. (2018) was consistent with autosomal dominant inheritance.
In a large Norwegian family with autosomal dominant nonsyndromic progressive high-tone hearing loss, Fagerheim et al. (1996) found linkage of the disorder to chromosome 1q21-q23. A maximum lod score of 7.65 at theta = 0 was obtained with the microsatellite marker D1S196. Fagerheim et al. (1996) reported that there are several candidate genes located in 1q21-q23, including LMX1A and POU2F1 (164175). They noted that the POU3F4 gene (300039) is involved in X-linked deafness (304400) and that the POU2F1 gene is located on chromosome 1 only 0.8-cM from the D1S196 marker which gave the highest lod score with DFNA7. They noted further that the POU genes encode a family of DNA-binding transcription factors with 3 domains in common. The POU2F1 gene was reported to be expressed in the cochlea during rat embryogenesis, consistent with its contribution to inner ear development.
In affected members of 2 unrelated Dutch families with DFNA7, Wesdorp et al. (2018) identified heterozygous missense mutations at highly conserved residues in the LMX1A gene (V241L, 600298.0001 and C97S, 600298.0002). Functional studies of the variant and studies of patient cells were not performed, and the authors postulated haploinsufficiency as a pathogenetic mechanism. However, Wesdorp et al. (2018) noted that Lmx1a heterozygous mutant mice have normal hearing (see ANIMAL MODEL and Steffes et al., 2012), which is not supportive of haploinsufficiency as the disease mechanism.
Bergstrom et al. (1999) characterized the phenotype of the recessive 'dreher' (dr) mutant mouse, which was later demonstrated to be caused by mutation in the Lmx1a gene (Millonig et al., 2000). Mice homozygous for the dr allele have ataxic gait, circling behavior, impaired righting reflex, hyperactivity, inner ear defects, deafness, and pigmentation abnormalities. Other features include cerebellar hypoplasia, cerebellar foliation and lamination abnormalities, neocortical disruptions of neuronal migration, underdeveloped Mullerian duct derivatives, and skeletal and skull defects. Bergstrom et al. (1999) mapped the dr locus to chromosome 1 in a region that shows syntenic homology with human chromosome 1q21-q23.
In the vertebrate central nervous system, a cascade of signals that originates in the ectoderm adjacent to the neural tube is propagated by the roof plate to dorsalize the neural tube. Millonig et al. (2000) reported that the phenotype of a spontaneous neurologic mutant mouse, called 'dreher' (dr), results from a failure of the roof plate to develop. Dorsalization of the neural tube is consequently affected: dorsal interneurons in the spinal cord and granule neurons in the cerebellar cortex are lost, and the dorsal vertebral neural arches fail to form. Millonig et al. (2000) used positional cloning to identify the gene mutant in dreher and found that the Lim homeodomain protein Lmx1a is affected in 3 different alleles of dreher. Lmx1a is expressed in the roof plate along the neuraxis during development of the central nervous system and is required for the development of the roof plate and, in turn, for specification of dorsal cell fates in the central nervous system and developing vertebrae.
Steffes et al. (2012) reported that mice homozygous for either the spontaneous mutanlallemand (mtl) mutation or the spontaneous belly spot and deafness (bsd) mutation had similar phenotypes. Homozygotes exhibited circling, head bobbing, and hyperactivity, and were smaller with short tails and white belly patches compared with wildtype. Mutant mice lacked a Preyer reflex, had severe morphologic defects of inner ear, and were profoundly deaf. Heterozygous mice had normal hearing. Complementation tests suggested that both mtl and bsd were mutant alleles of the Lmx1a gene. The authors identified the mtl mutation as a point mutation in the 3-prime splice site of exon 4 of Lmx1a and the bsd mutation as a genomic deletion including exon 3 of Lmx1a. Quantitative RT-PCR analysis revealed that Lmx1a transcripts in both mtl and bsd mutants were significantly downregulated compared with wildtype.
Bergstrom, D. E., Gagnon, L. H., Eicher, E. M. Genetic and physical mapping of the Dreher locus on mouse chromosome 1. Genomics 59: 291-299, 1999. [PubMed: 10444330, related citations] [Full Text]
Fagerheim, T., Nilssen, O., Raeymaekers, P., Brox, V., Moum, T., Elverland, H. H., Teig, E., Omland, H. H., Fostad, G. K., Tranebjaerg, L. Identification of a new locus for autosomal dominant non-syndromic hearing impairment (DFNA7) in a large Norwegian family. Hum. Molec. Genet. 5: 1187-1191, 1996. [PubMed: 8842739, related citations] [Full Text]
Millonig, J. H., Millen, K. J., Hatten, M. E. The mouse Dreher gene Lmx1a controls formation of the roof plate in the vertebrate CNS. Nature 403: 764-769, 2000. [PubMed: 10693804, related citations] [Full Text]
Steffes, G., Lorente-Canovas, B., Pearson, S., Brooker, R. H., Spiden, S., Kiernan, A. E., Guenet, J. L., Steel, K. P. Mutanlallemand (mtl) and belly spot and deafness (bsd) are two new mutations of Lmx1a causing severe cochlear and vestibular defects. PLoS One 7: e51065, 2012. Note: Electronic Article. [PubMed: 23226461, related citations] [Full Text]
Wesdorp, M., de Koning Gans, P. A. M., Schraders, M., Oostrik, J., Huynen, M. A., Venselaar, H., Beynon, A. J., van Gaalen, J., Piai, V., Voermans, N., van Rossum, M. M., Hartel, B. P., and 14 others. Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction. Hum. Genet. 137: 389-400, 2018. [PubMed: 29754270, related citations] [Full Text]
ORPHA: 90635; DO: 0110591;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q23.3 | Deafness, autosomal dominant 7 | 601412 | Autosomal dominant | 3 | LMX1A | 600298 |
A number sign (#) is used with this entry because of evidence that autosomal dominant deafness-7 (DFNA7) is caused by heterozygous mutation in the LMX1A gene (600298) on chromosome 1q22.
Autosomal dominant deafness-7 (DFNA7) is a form of progressive sensorineural hearing loss with highly variable age at onset and severity, even within families. The age at onset ranges from congenital to mid-adulthood. Some patients may have associated vertigo (summary by Wesdorp et al., 2018).
Fagerheim et al. (1996) described a large Norwegian family with autosomal dominant nonsyndromic progressive high-tone hearing loss. In the majority of affected family members examined with successive audiograms, the hearing loss was greater than 45 dB by age 15 years. Linkage analysis was performed in this family (see MAPPING), but additional genetic and DNA studies were not performed.
Wesdorp et al. (2018) reported 2 large unrelated families of Dutch origin in which 7 individuals had autosomal dominant nonsyndromic sensorineural hearing loss. The age at onset and the phenotype were highly variable, even within families. Two unrelated patients had onset at birth, 1 had childhood onset, 1 had onset at puberty, and 3 had onset between 26 and 35 years of age. The hearing loss, which was progressive for most patients, was mild to profound and associated with a downward sloping audiogram. Four patients had vestibular involvement with evidence of hyporeflexia manifest as vertigo and tinnitus; oculomotor testing was normal.
The transmission pattern of DFNA7 in the families reported by Wesdorp et al. (2018) was consistent with autosomal dominant inheritance.
In a large Norwegian family with autosomal dominant nonsyndromic progressive high-tone hearing loss, Fagerheim et al. (1996) found linkage of the disorder to chromosome 1q21-q23. A maximum lod score of 7.65 at theta = 0 was obtained with the microsatellite marker D1S196. Fagerheim et al. (1996) reported that there are several candidate genes located in 1q21-q23, including LMX1A and POU2F1 (164175). They noted that the POU3F4 gene (300039) is involved in X-linked deafness (304400) and that the POU2F1 gene is located on chromosome 1 only 0.8-cM from the D1S196 marker which gave the highest lod score with DFNA7. They noted further that the POU genes encode a family of DNA-binding transcription factors with 3 domains in common. The POU2F1 gene was reported to be expressed in the cochlea during rat embryogenesis, consistent with its contribution to inner ear development.
In affected members of 2 unrelated Dutch families with DFNA7, Wesdorp et al. (2018) identified heterozygous missense mutations at highly conserved residues in the LMX1A gene (V241L, 600298.0001 and C97S, 600298.0002). Functional studies of the variant and studies of patient cells were not performed, and the authors postulated haploinsufficiency as a pathogenetic mechanism. However, Wesdorp et al. (2018) noted that Lmx1a heterozygous mutant mice have normal hearing (see ANIMAL MODEL and Steffes et al., 2012), which is not supportive of haploinsufficiency as the disease mechanism.
Bergstrom et al. (1999) characterized the phenotype of the recessive 'dreher' (dr) mutant mouse, which was later demonstrated to be caused by mutation in the Lmx1a gene (Millonig et al., 2000). Mice homozygous for the dr allele have ataxic gait, circling behavior, impaired righting reflex, hyperactivity, inner ear defects, deafness, and pigmentation abnormalities. Other features include cerebellar hypoplasia, cerebellar foliation and lamination abnormalities, neocortical disruptions of neuronal migration, underdeveloped Mullerian duct derivatives, and skeletal and skull defects. Bergstrom et al. (1999) mapped the dr locus to chromosome 1 in a region that shows syntenic homology with human chromosome 1q21-q23.
In the vertebrate central nervous system, a cascade of signals that originates in the ectoderm adjacent to the neural tube is propagated by the roof plate to dorsalize the neural tube. Millonig et al. (2000) reported that the phenotype of a spontaneous neurologic mutant mouse, called 'dreher' (dr), results from a failure of the roof plate to develop. Dorsalization of the neural tube is consequently affected: dorsal interneurons in the spinal cord and granule neurons in the cerebellar cortex are lost, and the dorsal vertebral neural arches fail to form. Millonig et al. (2000) used positional cloning to identify the gene mutant in dreher and found that the Lim homeodomain protein Lmx1a is affected in 3 different alleles of dreher. Lmx1a is expressed in the roof plate along the neuraxis during development of the central nervous system and is required for the development of the roof plate and, in turn, for specification of dorsal cell fates in the central nervous system and developing vertebrae.
Steffes et al. (2012) reported that mice homozygous for either the spontaneous mutanlallemand (mtl) mutation or the spontaneous belly spot and deafness (bsd) mutation had similar phenotypes. Homozygotes exhibited circling, head bobbing, and hyperactivity, and were smaller with short tails and white belly patches compared with wildtype. Mutant mice lacked a Preyer reflex, had severe morphologic defects of inner ear, and were profoundly deaf. Heterozygous mice had normal hearing. Complementation tests suggested that both mtl and bsd were mutant alleles of the Lmx1a gene. The authors identified the mtl mutation as a point mutation in the 3-prime splice site of exon 4 of Lmx1a and the bsd mutation as a genomic deletion including exon 3 of Lmx1a. Quantitative RT-PCR analysis revealed that Lmx1a transcripts in both mtl and bsd mutants were significantly downregulated compared with wildtype.
Bergstrom, D. E., Gagnon, L. H., Eicher, E. M. Genetic and physical mapping of the Dreher locus on mouse chromosome 1. Genomics 59: 291-299, 1999. [PubMed: 10444330] [Full Text: https://doi.org/10.1006/geno.1999.5873]
Fagerheim, T., Nilssen, O., Raeymaekers, P., Brox, V., Moum, T., Elverland, H. H., Teig, E., Omland, H. H., Fostad, G. K., Tranebjaerg, L. Identification of a new locus for autosomal dominant non-syndromic hearing impairment (DFNA7) in a large Norwegian family. Hum. Molec. Genet. 5: 1187-1191, 1996. [PubMed: 8842739] [Full Text: https://doi.org/10.1093/hmg/5.8.1187]
Millonig, J. H., Millen, K. J., Hatten, M. E. The mouse Dreher gene Lmx1a controls formation of the roof plate in the vertebrate CNS. Nature 403: 764-769, 2000. [PubMed: 10693804] [Full Text: https://doi.org/10.1038/35001573]
Steffes, G., Lorente-Canovas, B., Pearson, S., Brooker, R. H., Spiden, S., Kiernan, A. E., Guenet, J. L., Steel, K. P. Mutanlallemand (mtl) and belly spot and deafness (bsd) are two new mutations of Lmx1a causing severe cochlear and vestibular defects. PLoS One 7: e51065, 2012. Note: Electronic Article. [PubMed: 23226461] [Full Text: https://doi.org/10.1371/journal.pone.0051065]
Wesdorp, M., de Koning Gans, P. A. M., Schraders, M., Oostrik, J., Huynen, M. A., Venselaar, H., Beynon, A. J., van Gaalen, J., Piai, V., Voermans, N., van Rossum, M. M., Hartel, B. P., and 14 others. Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction. Hum. Genet. 137: 389-400, 2018. [PubMed: 29754270] [Full Text: https://doi.org/10.1007/s00439-018-1880-5]
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