A Molecular Vision
Research Report

Fine Mapping of the Usher Syndrome Type IC to Chromosome 11p14 and Identification of Flanking Markers by Haplotype Analysis

R. Ayyagari1, Y.Li1, R.J.H.Smith2, M.Z. Pelias3, and J.F.Hejtmancik1*

1. National Eye Institute, National Institutes of Health
2. Department of Otolaryngology - Head and neck surgery, University of Iowa
3. Department of Biometry and Genetics, Louisiana State University Medical Center
*Corresponding author email: f3h@helix.nih.gov

Purpose: To refine the map position of the Usher syndrome type 1C (USH1C) locus to 11p14-p15.1 in the French-Acadian population settled in Louisiana.
Methods: Linkage and haplotype analysis of Ush1C in the French-Acadian families from southwestern Louisiana was carried out using additional markers known to map to the USH1C interval. Markers localized to 11p were also mapped on the J1 somatic cell hybrid panel. This analysis also helped to localize precisely the USH1C interval.
Results: New flanking markers for USH1C have been identified, localizing the USH1C gene to a 1 cM interval between markers D11S1397 and D11S1888. Markers D11S1890 and D11S1888 were placed within the USH1C interval. Analysis of all the markers in the USH1C region flanked by D11S1397 and D11S1888 on the J1 somatic cell hybrid panel localized USH1C to the upper half of chromosome 11p14.
Conclusion: The Usher Syndrome type 1C gene has been localized to a 1 cM interval between the markers D11S1397 and D11S1888 on chromosome 11p14.


The Usher syndromes (Ush) are a group of autosomal recessive disorders characterized by congenital sensorineural hearing impairment and retinitis pigmentosa. In the United States the frequency of Ush has been estimated at 4.4 per 100,000, making Ush the most common cause of deaf-blindness in developed countries (3). Based on clinical symptoms, three distinct types of Ush have been described (21).

Usher syndrome type I (Ush1) consists of profound congenital hearing impairment usually associated with unintelligible speech, early onset of retinitis pigmentosa, and vestibular dysfunction. In Usher syndrome type II (Ush2), deafness is more moderate so that speech is intelligible and the onset of retinitis pigmentosa tends to be delayed to the second or third decade. Vestibular function is normal in Ush2. In Usher syndrome type III (Ush3), both the sensorineural hearing loss and retinitis pigmentosa are progressive over time.

Genes causing Ush1, Ush2 and Ush3 have been mapped to five different chromosomal loci (10, 12, 13, 15, 18, 20). The existence of at least two additional loci for Ush type I and Ush type II is suggested by the observation that Ush in some of the families classified as type I and type II based on clinical symptoms have been excluded >from the known Usher syndrome loci (2, 4). These observations reflect the genetic heterogeneity of the various forms of Usher syndrome.

There are three different known loci for Ush type I (10,20). One of these, Usher syndrome type 1B on chromosome 11q, is myosin VIIA (22). The gene causing Usher syndrome type I in the French- Acadian population of Louisiana (USH1C) has been localized to a 5 cM interval between the markers D11S861 and D11S899 on the p arm of chromosome 11(1,11), a locus for Ush so far not detected in any other population. There is an unusually high incidence of Usher syndrome in the French-Acadian population that was resettled in Louisiana after France ceded Canada to Great Britain. A persuasive case has been made that the high incidence of Ush resulting from a unique locus in this population is due to a founder effect. If that is the case, chromosomes bearing the USH1C mutation would be expected to share a common haplotype in the USH1C region. Here we use linkage mapping and haplotype analysis in Ush1 patients from the French-Acadian population to localize the USH1C gene to a region of approximately 1 cM interval of chromosome 11p14.


Clinical Studies: Seven Acadian families with a history of Usher syndrome and individual affected patients with a history of Usher syndrome in their families were studied in detail (20). Affected individuals and their family members underwent a detailed physical examination including a battery of tests suggested for the clinical diagnosis of Ush (19) including the Bruininks-Oseretsky subtests of balance function, an otologic examination, and ice-water calorics using Frenzel's glasses to prevent fixation and to facilitate observation.

DNA and PCR analysis: Blood samples were collected from cooperative family members. DNA was isolated from blood or transformed cell lines using phenol/chloroform extraction as described previously (20). PCR and electrophoresis was performed as described earlier (20). Alleles were scored by three independent readers without reference to affectation status or pedigree, with any disagreement resulting initially in reevaluation of those observations. If that did not resolve the interpretation, the marker was analyzed again.

Linkage analysis: The LINKAGE program package version 5.1 was used for linkage analysis (14) with MLINK and ILINK used for two point analysis. USH1C was assumed to be a fully penetrant autosomal recessive trait with an affected allele frequency of 0.001. Marker allele frequencies were taken from the Genome Data Base at the Welch Library, Johns Hopkins University.

Chromosomal sublocalization of microsatellite markers: Seven somatic cell hybrids (J1, J11, 4B, J8, J9, J23, J24) containing parts of human chromosome 11 (8) were used for the regional localization of markers on chromosome 11. Genomic DNA isolated >from chromosome 11 hybrid cell lines was used as template in the PCR reaction carried out with the primers for microsatellite markers described in the Genome Data Base.


Localization of microsatellite markers: Markers D11S1397, D11S902, D11S921, D11S1890, D11S1888 and D11S1310 were localized to the 'g' segment of chromosome 11p, which spans the upper half of the 11p14 region. D11S861 and D11S419 were localized to the 'f' segment which covers 11p15.1 as described by Glasser et al. (8).

Linkage Analysis: Lod scores from the two-point analysis of chromosome 11p microsatellite markers with USH1C in French-Acadian families are shown in Table 1. All the markers in this region show maximum lod scores greater than 1.26 without recombination (Table 1). The highest lod scores obtained were with markers D11S902 (Zmax = 6.44 at theta = 0.00) and D11S1888 (Zmax = 6.40 at theta = 0.0).

Table 1: Two point lod scores of 11p microsatellite markers versus USH1C in French-Acadian families. Marker order corresponds to Figure 1.
MARKER 0.00 0.01 0.02 0.03 0.04 0.05 0.10 0.20 0.30 Z max Theta
D11S861 omega 3.22 3.39 3.43 3.41 3.37 2.99 1.97 0.88 3.42 0.03
D11S419 2.95 2.83 2.77 2.71 2.65 2.58 2.25 1.54 0.82 2.95 0.00
D11S1397 1.26 1.22 1.18 1.14 1.10 1.06 0.87 0.50 0.21 1.26 0.00
D11S902 6.44 6.26 6.09 5.92 5.75 5.57 4.71 3.02 1.50 6.44 0.00
D11S921 3.31 3.24 3.16 3.08 3.00 2.92 2.51 1.67 0.86 3.31 0.00
D11S1890 2.26 2.20 2.13 2.07 2.01 1.95 1.64 1.06 0.54 2.26 0.00
D11S1888 6.40 6.23 6.05 5.88 5.71 5.53 4.66 2.97 1.47 6.40 0.00
D11S1310 3.84 3.74 3.63 3.53 3.43 3.32 2.81 1.79 0.88 3.84 0.00
D11S899 5.46 5.31 5.16 5.01 4.85 4.70 3.95 2.51 1.23 5.46 0.00
D11S928 omega 1.58 1.81 1.91 1.97 1.99 1.89 1.34 0.70 1.99 0.05

Haplotype analysis in Acadian Families: In order to localize the USH1C gene more precisely, haplotypes of chromosomes with the USH1C and normal alleles were determined. Haplotypes were constructed for markers in the USH1C region in the following order, as determined by linkage analysis and physical mapping: tel - D11S861 - D11S419 - D11S1397 - D11S902 - D11S921 -D11S1890 - D11S1888 - D11S1310 - cen (6,16,17). Haplotypes from 70 chromosomes with the USH1C mutation and 13 non-USH1C chromosomes from the French-Acadian population were determined. Individuals belonging to the Acadian USH1C families used in the original localization of the USH1C gene to chromosome 11(20) were used for haplotype analysis. Additional individuals not in families 1-7 were analyzed only if they were affected and then were assumed to have two chromosomes carrying the USH1C allele, consistent with autosomal recessive inheritance of Usher syndrome type 1C.

Of the 70 affected chromosomes, 56 had haplotype A as shown in Table 2. In contrast, haplotype A was not seen on any of the 13 chromosomes with the unaffected allele. One affected chromosome had haplotype B, which differs from haplotype A only by having allele 4 rather than 3 at the D11S861 locus. No chromosomes with the unaffected allele showed haplotype B. Seven additional chromosomes with the USH1C allele had haplotype C, which differs >from haplotype A at D11S1397, having allele 3 rather than allele 1. No chromosomes with the unaffected allele showed haplotype C. Four chromosomes carrying the USH1C mutation had haplotype D, which differs from haplotype A by having allele 2 rather than allele 4 at D11S1310. None of the chromosomes with the unaffected allele showed haplotype D. Two USH1C chromosome showed haplotype E, which differs from the consensus haplotype A by having allele 1 rather than 4 at the D11S1888 locus. In addition, the 2 chromosomes with haplotype E also have allele 3 at D11S1310. One chromosome with the USH1C mutation had haplotype F, which differs from haplotype A by having allele 1 at D11S130 locus rather than allele 4. None of the chromosomes with the unaffected allele carry haplotype E or F.

Table 2. Association of haplotypes with the USH1C mutation in the French-Acadian population of Louisiana. Alleles are named in a fashion consistent with that used in the CEPH database.
Markers Chromosomes
Haplotype D11S861 D11S419 D11S1397 D11S902 D11S921 D11S1890 D11S1888 D11S1310 USH(%) Normal(%)
A 3 2 1 4 3 2 4 4 55 (78.0) 0
B 4 2 1 4 3 2 4 4 1 (1.43) 0
C 3 2 3 4 3 2 4 4 7 (10.0) 0
D 3 2 1 4 3 2 4 2 4 (5.71) 0
E 3 2 1 4 3 2 1 3 2 (2.80) 0
F 3 2 1 4 3 2 4 1 1 (1.43) 0
2 2 3 3 3 1 1 3 0 1 (0.08)
1 2 3 2 2 4 2 4 0 1 (0.08)
4 2 1 2 3 2 2 3 0 1 (0.08)
2 1 1 2 1 5 1 4 0 1 (0.08)
5 2 1 3 3 1 3 4 0 1 (0.08)
1 1 1 2 2 2 1 1 0 1 (0.08)
1 1 3 2 3 2 2 1 0 1 (0.08)
4 1 1 3 1 2 1 2 0 1 (0.08)
1 2 1 2 1 3 1 2 0 1 (0.08)
1 1 1 2 3 2 2 5 0 1 (0.08)
1 1 1 1 3 3 3 3 0 1 (0.08)
2 2 3 3 1 2 1 3 0 1 (0.08)
6 1 2 2 3 2 2 2 0 1 (0.08)
___________ ___________
70 13

Most affected individuals were homozygous for all markers in the USH1C region, having two copies of the consensus haplotype A (Table 2; Example: individual 5 of
pedigree 101, see Fig. 1). A small number showed a single allele change from the consensus haplotype A indicating one copy of haplotype A and one copy of an alternative haplotype B-E differing by one allele (Examples: individual 11 of pedigree 102; individual 3 of pedigree 105, see Fig. 1). Finally, an affected individual not in families 1-7 was homozygous for all markers between D11S861 and D11S1310, but with two copies of haplotype C.

From the pedigree shown in Fig. 1, it was possible to determine the chromosomal haplotypes of 13 phenotypically normal parents of individuals affected by USH1C unambiguously. The haplotypes of the parental chromosomes not transmitted to the affected offspring were assumed not to contain the USH1C mutation and were taken as control haplotypes for the Acadian population. There was no consensus haplotype among these chromosomes and none of these 13 non-USH1C chromosomes resembled any of the USH1C associated haplotypes (Table 2).

[Figure 1] [Pedigree 101] [Pedigree 102] [Pedigree 103] [Pedigree 104] [Pedigree 105] [Pedigree 106] [Pedigree 107]
Note for Fig.1 and Pedigrees: Distinct haplotypes are represented by unique colors in pedigree figures. Non-recombinant affected chromosomes are blue.


Usher Syndrome type I C was initially localized to a 5.5 cM interval on the p arm of chromosome 11 bounded by the markers D11S861 and D11S899 (1, 11) using linkage analysis. Later the USH1C critical region was futher narrowed to the region between the markers D11S1397 and D11S1310 (16). Two new microsatellite markers, D11S1890 and D11S1888 have since been localized to the region between D11S902 and D11S1310 based on radiation hybrid mapping (5, 9). However the precise location of these markers with respect to the other markers on the existing linkage maps is not known. Preliminary evidence based on construction of a YAC contig across this region suggests that the likely order is Tel - D11S861 - D11S419 - D11S1397 - D11S902 - D11S921 - D11S1890 - D11S1888 - D11S1310 - D11S899 - Cen (17)

Two point linkage analysis of USH1C families with markers D11S1890 and D11S1888 gave lod scores of 2.26 and 6.40 respectively without recombination. These results localize the markers D11S1890 and D11S1888 close to the USH1C locus. Since obligate recombination events were observed with markers D11S861 and D11S928 in USH1C families from the French-Acadian population in Louisiana and the markers D11S1890 and D11S1888 showed no recombination, these two markers could be localized to the region flanked by the markers D11S861 and D11S928.

The reported order of the markers in this region on linkage maps was Tel - D11S861 - D11S419 - D11S1397 - D11S902 - D11S921 - D11S1310 - D11S899 - Cen(7, 16). The markers D11S1890 and D11S1888 map to the g segment of the J1 hybrid panel, as do the markers D11S1397, D11S902, D11S921, D11S1301 and D11S899. The markers D11S861 and D11S419 map to the f segment of chromosome 11p. This suggests that D11S1890 and D11S1888 are located between D11S419 and D11S899. These results are in agreement with the reported location of these to the region bounded by D11S902 and D11S1310 (5, 9). Thus, the available linkage data, results of the J1 hybrid panel, and our physical mapping efforts are all consistent with the order:Tel - D11S861 - D11S419 - D11S1397 - D11S902 - D11S921 - D11S1890 - D11S1888 - D11S1310 - Cen.

Haplotype analysis of 70 USH1C chromosomes carrying the disease allele for USH1C and 13 chromosomes carrying normal allele >from the French-Acadian population was carried out with the map: Tel - D11S861 - D11S419 - D11S1397 - D11S902 - D11S921 - D11S1890 - D11S1888 - D11S1310 - Cen. Seventy percent of the affected chromosomes possess a common haplotype for markers between D11S1397 to D11S1888. However, the occurrence of variant haplotypes in some chromosomes with the USH1C allele restricts the USH1C to the approximately 1cM interval bounded by D11S1397 and D11S188. These results also localize the USH1C locus to the upper one third of 11p14 based on the analysis of these flanking markers on the J1 hybrid panel. The precise localization of USH1C locus to a smaller region helps in construction of a physical map of the region encompassing the USH1C locus and isolation of the gene responsible for Usher Syndrome type I in the French-Acadian population.


We thank Dr. Carol Jones for kindly providing the chromosome 11, J1 somatic cell hybrid panel lines.


1. Ayyagari R, Smith R.J.H., Polymeropoulos M, et al. Linkage and Haplotype Analysis and Physical Mapping of the USH1C gene. [Abstract] Invest Ophthalmol Vis Sci 1994;35:(4)2143

2. Ayyagari, R, Smith, RJH, Lee, EC, Kimberling, WJ, Bird, A, Hejtmancik, JF. Heterogeneity of Usher Syndrome Type I. In JG Hollyfield, RE Anderson, MM LaVail(eds.), Retinal Degeneration, Plenum Press, New York (1993) pp. 127-33.

3. Boughman, JA, Caldwell, RJ. Genetic and clinical characterization of a survey population with retinitis pigmentosa. In Clinical, Structural, and Biochemical Advances in Hereditary Eye Disorders, Alan R. Liss Inc, New York (1982) pp. 147-66.

4. Dahl SP, Weston MD, Kimberling WJ, et al. Possible genetic heterogeneity of Usher syndrome type 2: a family unlinked to chromosome 1q markers.. [Abstract] Am J Hum Genet 1991;49 supl.:200

5. Fantes, JA, Oghene, K, Boyle, S, Danes, S, Fletcher, JM, Bruford, EA, Williamson, K, Seawright, A, Schedl, A, Hanson, I, et al, A High-Resolution Integrated Physical, Cytogenetic, and Genetic Map of Human Chromosome 11: Distal p13 to Proximal p15.1, Genomics 25 (1995) 447-61.PubMedLink

6. Glaser B, Chiu K C, Liu L, Anker R, Nestorowicz A, Cox N J, Landau H, Kaiser N, Thornton P S, Stanley C A, et al, Recombinant mapping of the familial hyperinsulinism gene to an 0.8 cM region on chromosome 11p15.1 and demonstration of a founder effect in Ashkenazi Jews., Human Molec. Genet 4 (1995) 879-86.PubMedLink

7. Glaser, B, Chiu, KC, Anker, R, Nestorowicz, A, Landau, H, Ben-Bassat, H, Shlomai, Z, Kaiser, N, Thornton, PS, Stanley, CA, Familial hyperinsulinism maps to chromosome 11p14-15.1, 30 cM centromeric to the insulin gene, Nat. Genet 7 (1994) 185-8. PubMedLink

8. Glaser, T, Housman, D, Lewis, WH, Gerhard, D, Jones, C, A fine-structure deletion map of human chromosome 11p: analysis of J1 series hybrids, Somatic Cell Mol. Genet. 15 (1989) 477-501. PubMedLink

9. James, MR, Richard, CW, 3rd, Schott, JJ, Yousry, C, Clark, K, Bell, J, Terwilliger, JD, Hazan, J, Dubay, C, Vignal, A, A radiation hybrid map of 506 STS markers spanning human chromosome 11, Nat. Genet 8 (1994) 70-6. PubMedLink

10. Kaplan, J, Gerber, S, Bonneau, D, Rozet, JM, Delrieu, O, Briard, ML, Dollfus, H, Ghazi, I, Dufier, JL, Frezal, J, A gene for Usher syndrome type I (USH1A) maps to chromosome 14q, Genomics 14 (1992) 979-87. PubMedLink

11. Keats, BJ, Nouri, N, Pelias, MZ, Deininger, PL, Litt, M, Tightly linked flanking microsatellite markers for the Usher syndrome type I locus on the short arm of chromosome 11, Am. J Hum Genet 54 (1994) 681-6. PubMedLink

12. Kimberling, WJ, Moller, CG, Davenport, S, Priluck, IA, Beighton, PH, Greenberg, J, Reardon, W, Weston, MD, Kenyon, JB, Grunkemeyer, JA, Linkage of Usher syndrome type I gene (USH1B) to the long arm of chromosome 11, Genomics 14 (1992) 988-94. PubMedLink

13. Kimberling, WJ, Weston, MD, Moller, C, Davenport, SLH, Shugart, YY, Priluck, IA, Martini, A, Smith, RJH, Localization of Usher syndrome Type II to chromosome 1q, Genomics 7 (1990) 245-9. PubMedLink

14. Lathrop, GM, Lalouel, JM, Easy calculations of lod scores and genetic risks on small computers, Am. J. Hum. Genet. 36 (1984) 460-5. PubMedLink

15. Lewis, RA, Otterud, B, Stauffer, D, Lalouel, JM, Leppert, M, Mapping recessive ophthalmic diseases: linkage of the locus for Usher syndrome type II to a DNA marker on chromosome 1q, Genomics 7 (1990) 250-6. PubMedLink

16. Nouri N, Risch N.J, Pelias M.Z, et al. Predicting the age of the mutation for Usher Syndrome type I in the Acadian population. [Abstract] Am J Hum Genet 1995;55:(3)a160

17. Radha Ayyagari, Ann Nestorowicz, Yan Li, Craig Chinault, Settara Chandrasekharappa, Peter Van Tuinen, D.LePaslier, D.Cohen, Richard J.Smith, M.Allan Permutt, et al, Construction of a YAC contig encompassing the Usher Syndrome type 1C and Familial Hyperinsulinism Loci on chromosome 11p14-15.1(in preparation)

18. Sankila, EM, Pakarinen, L, Kaariainen, H, Aittomaki, K, Karjalainen, S, Sistonen, P, De La Chapelle, A, Assignment of an Usher syndrome type III (USH3) gene to chromosome 3q, Hum Mol. Genet 4 (1995) 93-8. PubMedLink

19. Smith, RJ, Berlin, CI, Hejtmancik, JF, Keats, BJ, Kimberling, WJ, Lewis, RA, Moller, CG, Pelias, MZ, Tranebjaerg, L, Clinical diagnosis of the Usher syndromes. Usher Syndrome Consortium, Am. J. Med. Genet. 50 (1994) 32-8. PubMedLink

20. Smith, RJH, Lee, EC, Kimberling, WJ, Daiger, SP, Pelias, MZ, Keats, BJB, Jay, M, Bird, A, Reardon, W, Guest, M, et al, Localization of two genes for Usher syndrome type I to chromosome 11, Genomics 14 (1992) 995-1002. PubMedLink

21. Smith, RJH, Pelias, MZ, Daiger, SP, Keats, B, Kimberling, W, Hejtmancik, JF, Clinical variability and genetic heterogeneity within the Acadian Usher population, Amer. J. Med. Genet. 43 (1992) 964-9. PubMedLink

22. Weil, D, Blanchard, S, Kaplan, J, Guilford, P, Gibson, F, Walsh, J, Mburu, P, Varela, A, Levilliers, J, Weston, MD, Defective myosin VIIA gene responsible for Usher syndrome type 1B, Nature 374 (1995) 60-1. PubMedLink

Return to Molecular Vision homepage
Received xx September 1995 | Revised 19 October 1995 | Accepted 24 October 1995 | Uploaded 25 October 1995
Referencing Note: This article may be referenced as: Mol. Vis. 1:2, 1995.
Alternatively, this article may be referenced by its unique URL: http://www.emory.edu/molvis/v1/ayyagari

© 1995 Molecular Vision