|Molecular Vision 2004;
Received 9 August 2004 | Accepted 22 November 2004 | Published 24 November 2004
Genetic analysis of a four generation Indian family with Usher syndrome: a novel insertion mutation in MYO7A
William J. Kimberling,2
Conjeevaram P. Venkatesh3
1Department of Molecular Reproduction, Development, and Genetics, Indian Institute of Science, Bangalore, India; 2Center for the Study and Treatment of Usher Syndrome, Boys Town National Research Hospital, Omaha, NE; 3Minto Ophthalmic Hospital, Bangalore, India
Correspondence to: Dr. Arun Kumar, Department of Molecular Reproduction, Development, and Genetics, Indian Institute of Science, Bangalore, 560 012, India; Phone: 91-80-2 293 2998; FAX: 91-80-2 360 0999; email: firstname.lastname@example.org
Purpose: Usher syndrome (USH) is a rare autosomal recessive disorder characterized by deafness and retinitis pigmentosa. The purpose of this study was to determine the genetic cause of USH in a four generation Indian family.
Methods: Peripheral blood samples were collected from individuals for genomic DNA isolation. To determine the linkage of this family to known USH loci, microsatellite markers were selected from the candidate regions of known loci and used to genotype the family. Exon specific intronic primers for the MYO7A gene were used to amplify DNA samples from one affected individual from the family. PCR products were subsequently sequenced to detect mutation. PCR-SSCP analysis was used to determine if the mutation segregated with the disease in the family and was not present in 50 control individuals.
Results: All affected individuals had a classic USH type I (USH1) phenotype which included deafness, vestibular dysfunction and retinitis pigmentosa. Pedigree analysis suggested an autosomal recessive mode of inheritance of USH in the family. Haplotype analysis suggested linkage of this family to the USH1B locus on chromosome 11q. DNA sequence analysis of the entire coding region of the MYO7A gene showed a novel insertion mutation c.2663_2664insA in a homozygous state in all affected individuals, resulting in truncation of MYO7A protein.
Conclusions: This is the first study from India which reports a novel MYO7A insertion mutation in a four generation USH family. The mutation is predicted to produce a truncated MYO7A protein. With the novel mutation reported here, the total number of USH causing mutations in the MYO7A gene described to date reaches to 75.
Usher syndrome (USH) named after the British ophthalmologist Charles Usher  is the most common hereditary form of combined blindness and deafness . It is a rare disorder with an incidence of 3.5/100,000 in Scandinavia  to 4.4/100,000 in the USA . It shows an autosomal recessive mode of inheritance. According to clinical symptoms, USH is classified into three types: USH type I, USH type II and USH type III. USH type I is the most severe form and is characterized by severe to profound congenital sensorineuronal deafness, constant vestibular dysfunction (balance deficiency) and prepubertal onset of retinitis pigmentosa (RP). USH type II has a congenital mild to moderate hearing loss, normal vestibular responses, and RP during the second decade of life. USH type III has a progressive hearing loss, variable vestibular problems and variable RP .
USH type I is genetically heterogeneous with seven known loci: USH1A on chromosome 14q , USH1B on chromosome 11q , USH1C on chromosome 11p15.1 , USH1D on chromosome 10q21-22 , USH1E on chromosome 21q21 , USH1F on chromosome 10  and USH1G on chromosome 17q24-25 . USH1B is the most common subtype and accounts for about 70% of all type I cases . Of seven loci for USH type I, genes for only five loci (USH1B, USH1C, USH1D, USH1F, and USH1G) have been isolated so far. USH1B is known to be caused by mutations in an unconventional myosin, the motor protein myosin VIIA . Atypical USH, in which the hearing loss is progressive, is also known to be caused by mutations in the myosin VIIA . USH1C, USH1D, USH1F, and USH1G are caused by mutations in PDZ73 (harmonin), CDH23 (cadherin 23), PCDH15 (Procadherin), and SANS genes, respectively [16-19].
USH type II is genetically heterogeneous with three known loci: USH2A on chromosome 1q41 , USH2B on chromosome 3p22-24.2 , and USH2C on chromosome 5q14.3-21.3 . The USH2A gene coding for extracellular protein usherin has been shown to be responsible for disease phenotype linked to the USH2A locus . Weston et al.  have recently isolated the gene, VLGR1 (MASS1) for the USH2C locus. A single locus, USH3 has been mapped to chromosome 3q21-25 for USH type III . Joensuu et al.  have identified the gene for this locus, which codes for a cell-cell adhesion protein called clarin-1.
Genetic analysis of USH has been carried out in patients from several countries [5-35]. However, there is no report on the genetic analysis of any Indian family with USH. We report here genetic analysis of a four generation Indian family with members suffering from USH for the first time. Haplotype analysis suggested mapping of this family to the USH1B locus. DNA sequence analysis identified a novel insertion mutation in the MYO7A gene in this family.
We have ascertained a four generation consanguineous USH family from Bangalore, India (Figure 1). Thirteen living family members, including five affected individuals, were recruited for the study. Each individual underwent a detailed clinical examination for Usher syndrome. No other abnormalities were noticed in affected individuals other than Usher syndrome symptoms and their development and intelligence appeared to be normal. Informed consent was obtained for research following the guidelines of the Indian Council of Medical Research, New Delhi.
Genotyping and mutation analysis
Peripheral blood samples were drawn from all 13 individuals in Vacutainer EDTA tubes (Beckton-Dickinson, Franklin Lakes, NJ). Genomic DNA samples were isolated from peripheral blood samples using a Wizard® genomic DNA extraction kit (Promega, Madison, WI). Because this family is consanguineous, homozygosity by descent was sought and used to assess evidence of linkage to a particular locus. Linkage of consanguineous families to a locus is based on the observation that if all affected individuals of a family had the same homozygous haplotype for a locus, the family was considered linked. In order to determine if this family is linked to one of the known loci for Usher syndrome type 1, two to seven microsatellite markers were selected from their candidate regions and used to genotype the family [5,12]. The markers selected from the seven known loci are shown in Table 1. Genotyping was performed as described in Kumar et al. .
For mutation analysis of the MYO7A gene, a set of 48 PCR primers, which cover the entire coding region of this gene along with intron/exon junctions, were used. Sequences and PCR conditions of these primers are provided in Table 2. Mutation in this gene was identified by sequencing the PCR products from one affected individual from the family on an ABIprism A310 automated sequencer (PE Biosystems, Foster City, CA). Prior to sequencing, PCR products were purified on Auprep® PCR Purification columns (Life Technology Pvt. Ltd., New Delhi, India). PCR-SSCP analysis was used to see if the mutation segregated with the disease in the family and was not present in 50 normal control individuals as described in Kumar et al. .
All the five affected individuals had a classic USH1 phenotype which included congenital and profound sensorineural hearing loss with no vestibular response, and retinitis pigmentosa (RP). All five affected individuals started walking approximately at the age of five years. The age of the onset of RP was prepubertal in all affected individuals, which ranged from four to six years. All affected individuals had similar findings on examination with a small variation in visual acuity and visual fields (Table 3). All had excellent best corrected visual acuities ranging from 6/6p to 6/12. Visual fields (as determined by confrontational testing and Octopus automated perimetry) were restricted in all affected individuals. The extent of visual field ranged from 10° to 30°. The worst restriction was seen in the oldest affected individual IV-1. Anterior segment examination including the lens was normal in all affected individuals with normal pupillary reactions. Intraocular pressure measurements using Goldmann applanation tonometry were within normal limits for all affected individuals. Posterior segment findings were similar with all affected individuals showing features of central retinitis pigmentosa with arteriolar attenuation, disc pallor and tessellation of the fundus with bone spicule pigmentation in the posterior pole and equatorial fundus. A metallic sheen at the macula was seen in all affected individuals. However, macular function tests were normal in all affected individuals. The affected individual IV-4 had a longstanding total retinal detachment (probably secondary to trauma) in the left eye with only perception of light. Symptomatically, all five affected individuals complained of decreased night vision (nyctalopia). There were no other significant findings on neurological and other systemic examination.
The visual inspection of the pedigree suggested an autosomal recessive mode of inheritance in the family (Figure 1). Haplotype analysis using markers selected from the candidate regions of all seven known USH1 loci suggested linkage of this family to the USH1B locus only (Figure 1). A disease haplotype 2-1-3-2-2-1 for markers D11S1902, D11S4179, D11S4186, D11S4079, D11S906 and D11S911 was co-segregating with the disease consistent with a homozygous state in all five affected individuals (Figure 1), suggesting that USH in this family is caused by a mutation in the MYO7A gene. DNA sequence analysis of entire coding region of this gene in an affected individual IV-4 showed an insertion of A residue between nucleotide positions 2663 and 2664 (c.2663_2664insA) in exon 22 in a homozygous state (Figure 2A), resulting in a premature stop codon in exon 23 (Figure 2B). PCR-SSCP analysis showed cosegregation of the mutation with the disease in the family (Figure 2C). This change was not present in 50 normal control individuals (data not shown).
Our review of the literature on the total number of mutations reported to date in the MYO7A gene responsible for USH showed a total of 74 mutations with 48 being novel and 26 recurrent [13,14,27-35]. With the addition of the mutation reported in this study, the total number of known mutations in the MYO7A gene reaches to 75. In addition to USH causing mutations, four mutations in patients with autosomal recessive nonsyndromic deafness (DFNB2) [37,38] and four mutations in patients with autosomal dominant nonsyndromic deafness (DFNA11) [39-42] in the MYO7A gene have also been reported. Of 75 mutations that cause USH1B, 40 are missense, 16 are nonsense, 15 are deletions, and four are insertions. Although no mutations are detected in 12 of the 48 coding exons (exons 2, 10, 12, 20, 24, 26, 27, 32, 33, 34, 42, and 43), they are found to be scattered across the coding region, suggesting that mutation analysis in this gene will require evaluation of its complete coding region. The mutation, c.2663_2664insA in the present family is predicted to introduce a premature stop codon in exon 23 with a missense run of 18 amino acids starting from codon 889 in exon 22 (Figure 2B). The overall effect of this mutation is a premature truncation of MYO7A protein (Figure 2D). The mutated MYO7A protein is very unlikely to form dimers. In order to see if the insertion of the A residue has an affect on the splicing of the mutant MYO7A transcript, we carried out in silico analysis of putative exonic splicing enhancers and control elements in the normal and the mutant alleles using the RESCUE-ESE program . The analysis of the normal allele predicted three enhancers, CAAGAA, AAGAAG, and AGAAGG at the site of insertion in the normal allele. Whereas, it predicted one common, CAAGAA, and two different, AAGAAA and AGAAAG, enhancers in the mutant allele at the site of insertion (Figure 3). This suggests that the alteration of enhancers at the insertion site may influence splicing of the mutant MYO7A transcript in patients, although it remains to be experimentally proven.
The human MYO7A gene consists of 49 exons, the first being a noncoding one, and produces a 7.5 kb transcript . The MYO7A gene is expressed in cochlea and retina . It encodes a protein of 2,215 amino acids (230 kDa) . MYO7A protein contains an N-terminal head domain with ATP and actin binding sites followed by a 126 amino acid neck domain containing five IQ motifs serving as binding sites for calmodulin, a short 78 amino acid long coiled-coil domain for dimerization and a C-terminal tail region . As a result of the insertion mutation, MYO7A mutant protein is predicted to contain only 906 amino acids with last 18 amino acids being different (Figure 2D). This mutant protein lacks the tail region. The tail domain of MYO7A is believed to be largely responsible for its function . Recently, several proteins, such as MAP2B, RIα of PKA, Keap1, vezatin, MyRIP, and harmonin, have been identified that interact with different domains in the tail region of MYO7A [46-51], indicating that these proteins specify the cellular function of MYO7A. Further, MYO7A protein has been suggested to be targeted to the plasma membrane by its FERM domains in the tail region . Recently, it has been shown that MYO7A is a component of a supramolecular USH1 complex integrated in the plasma membrane via harmonin . The scaffold protein harmonin binds the MYO7A tail via its PDZ domain 1 . The supramolecular USH1 complex is necessary for the proper differentiation of the stereovilli in the mechanosensitive hair cells . Taken together, the absence of the tail region of mutant MYO7A protein will abrogate its function, resulting in the disease phenotype in patients reported here.
In summary, we have shown our results on the genetic analysis of a four generation Indian family with USH1. Our analysis suggested linkage of this family to the USH1B locus on chromosome 11q. Mutation analysis of the MYO7A gene revealed a novel insertion mutation in this family, resulting in premature truncation of the protein and disease phenotype in patients. Our review of the literature showed that the total number of USH causing mutations in the MYO7A gene reaches to 75. The information presented here will be useful to provide prenatal diagnosis and genetic counseling to the family and their relatives.
We are thankful to the members of the family for their participation in this study. This work was supported by grants from the University Grants Commission and the Department of Science and Technology, New Delhi.
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