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Homozygosity Mapping Reveals Mutations of GRXCR1 as a Cause of Autosomal- Recessive Nonsyndromic Hearing Impairment  Margit Schraders, Kwanghyuk Lee, Jaap.

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Presentation on theme: "Homozygosity Mapping Reveals Mutations of GRXCR1 as a Cause of Autosomal- Recessive Nonsyndromic Hearing Impairment  Margit Schraders, Kwanghyuk Lee, Jaap."— Presentation transcript:

1 Homozygosity Mapping Reveals Mutations of GRXCR1 as a Cause of Autosomal- Recessive Nonsyndromic Hearing Impairment  Margit Schraders, Kwanghyuk Lee, Jaap Oostrik, Patrick L.M. Huygen, Ghazanfar Ali, Lies H. Hoefsloot, Joris A. Veltman, Frans P.M. Cremers, Sulman Basit, Muhammad Ansar, Cor W.R.J. Cremers, Henricus P.M. Kunst, Wasim Ahmad, Ronald J.C. Admiraal, Suzanne M. Leal, Hannie Kremer  The American Journal of Human Genetics  Volume 86, Issue 2, Pages (February 2010) DOI: /j.ajhg Copyright © 2010 The American Society of Human Genetics Terms and Conditions

2 Figure 1 Homozygous Regions and Linkage Intervals within DFNB25
Schematic representation of chromosomal region 4p14-q12 showing the homozygous regions in families W and W and the linkage intervals for families DEM 4265 and DEM The overlapping region contains the GRXCR1 gene and exon 1 of the ATP8A1 gene. In addition, four ESTs are localized in the region, which are not further characterized. The Mb positions and chromosome bands were determined with the UCSC Genome Browser (NCBI build 36.1; hg18 annotation tracks, March 2006). The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

3 Figure 2 Mutation Analysis of GRXCR1 in arNSHI Patients
Partial sequences are shown of GRXCR1 from affected members of the different families and healthy controls. The predicted amino acid changes and the surrounding amino acids are indicated above the sequence. Mutated nucleotides are marked by an arrowhead. Reference sequences are NT_ for the nucleotide sequence and NP_ for the amino acid sequence. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

4 Figure 3 Alignment of the GRXCR1 Proteins of Different Species
(A) Overview of the conserved domains in GRXCR1 as predicted by different software tools. The GRX-like domain is predicted to be present by all three programs. However, the exact positions differ. (B) An alignment of GRXCR1 orthologs was made with ClustalW and Jalview,39,40 and part of the GRXCR1 protein is shown. Abbreviations are as follows: Hs, Homo sapiens; Pt, Pan troglodytes; Mm, Mus musculus; Rn, Rattus norvegicus; Gg, Gallus gallus; Dr, Danio rerio. Fully conserved amino acids are marked in dark gray, and less-conserved amino acids are in lighter colors. Accession numbers of the various protein sequences are as follows: Hs GRXCR1, NP_ ; Pt LOC461192, XP_ ; Mm Grxcr1, NP_ ; Rn Grxcr1, XP_ ; Gg LOC770624, XP_ ; Dr LOC , XP_ The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

5 Figure 4 Splicing Effect of the c.628-9C>A Mutation
Partial sequence of GRXCR1 cDNA from an affected member of family W and a healthy control. Additional nucleotides are present between exons 2 and 3, leading to a frameshift and a premature-stop codon, p.Gly210LeufsX5. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

6 Figure 5 GRXCR1 Expression Profile
Relative GRXCR1 mRNA expression determined by quantitative PCR in adult (A) and fetal (B) tissues. The relative expression values were determined with the delta delta Ct method. There is a highly preferential expression in fetal cochlea. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

7 Figure 6 Clinical Characterization of DFNB25 Families
(A–D) Representative audiograms of the right ear of affected individuals of families W and W at different ages. Dashed lines indicate free-field measurements. (E and F) Representative audiograms of affected individuals of families DEM 4265 and DEM 4349, obtained at the ages of 19 and 26 yrs, respectively. Circles and crosses represent the right and left ear, respectively. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

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