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Saima Riazuddin - One of the best experts on this subject based on the ideXlab platform.
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alterations of the cib2 calcium and integrin binding protein cause usher syndrome type 1j and Nonsyndromic Deafness dfnb48
Nature Genetics, 2012Co-Authors: Saima Riazuddin, Inna A Belyantseva, Arnaud P Giese, Artur A Indzhykulian, Sri Pratima Nandamuri, Rizwan Yousaf, Ghanshyam P Sinha, David TerrellAbstract:Zubair Ahmed and colleagues identify homozygous mutations in CIB2, a gene that encodes a calcium- and integrin-binding protein, that cause Usher syndrome type 1J and Nonsyndromic Deafness DFNB48. CIB2 is required for hair cell development and retinal photoreceptor cells in zebrafish and Drosophila melanogaster.
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dfnb79 reincarnation of a Nonsyndromic Deafness locus on chromosome 9q34 3
European Journal of Human Genetics, 2010Co-Authors: Shahid Y Khan, Saima Riazuddin, Zubair M Ahmed, Ahmad Usman Zafar, Robert J Morell, Atteeq U Rehman, Mohsin Shahzad, Nazir Ahmed, Andrew J. Griffith, Sheikh RiazuddinAbstract:Genetic analysis of an inbred Pakistani family PKDF280, segregating prelingual severe to profound sensorineural hearing loss, provided evidence for a DFNB locus on human chromosome 9q34.3. Co-segregation of the Deafness trait with marker D9SH159 was determined by a two-point linkage analysis (LOD score 9.43 at θ=0). Two additional large families, PKDF517 and PKDF741, co-segregate recessive Deafness with markers linked to the same interval. Haplotype analyses of these three families refined the interval to 3.84 Mb defined by D9S1818 (centromeric) and D9SH6 (telomeric). This interval overlaps with the previously reported DFNB33 locus whose chromosomal map position has been recently revised and assigned to a new position on chromosome 10p11.23–q21.1. The Nonsyndromic Deafness locus on chromosome 9q segregating in family PKDF280 was designated DFNB79. We are currently screening the 113 candidate DFNB79 genes for mutations and have excluded CACNA1B, EDF1, PTGDS, EHMT1, QSOX2, NOTCH1, MIR126 and MIR602.
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molecular basis of dfnb73 mutations of bsnd can cause Nonsyndromic Deafness or bartter syndrome
American Journal of Human Genetics, 2009Co-Authors: Saima Riazuddin, Saima Anwar, Martin Fischer, Zubair M Ahmed, Shahid Y Khan, Audrey G H Janssen, Ahmad Usman Zafar, Ute I SchollAbstract:BSND encodes barttin, an accessory subunit of renal and inner ear chloride channels. To date, all mutations of BSND have been shown to cause Bartter syndrome type IV, characterized by significant renal abnormalities and Deafness. We identified a BSND mutation (p.I12T) in four kindreds segregating Nonsyndromic Deafness linked to a 4.04-cM interval on chromosome 1p32.3. The functional consequences of p.I12T differ from BSND mutations that cause renal failure and Deafness in Bartter syndrome type IV. p.I12T leaves chloride channel function unaffected and only interferes with chaperone function of barttin in intracellular trafficking. This study provides functional data implicating a hypomorphic allele of BSND as a cause of apparent Nonsyndromic Deafness. We demonstrate that BSND mutations with different functional consequences are the basis for either syndromic or Nonsyndromic Deafness.
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DFNB79: reincarnation of a Nonsyndromic Deafness locus on chromosome 9q34.3
European Journal of Human Genetics, 2009Co-Authors: Shahid Y Khan, Saima Riazuddin, Ahmad Usman Zafar, Robert J Morell, Atteeq U Rehman, Mohsin Shahzad, Nazir Ahmed, Andrew J. Griffith, Zubair Ahmed, RiazuddinAbstract:Genetic analysis of an inbred Pakistani family PKDF280, segregating prelingual severe to profound sensorineural hearing loss, provided evidence for a DFNB locus on human chromosome 9q34.3. Co-segregation of the Deafness trait with marker D9SH159 was determined by a two-point linkage analysis (LOD score 9.43 at theta=0). Two additional large families, PKDF517 and PKDF741, co-segregate recessive Deafness with markers linked to the same interval. Haplotype analyses of these three families refined the interval to 3.84 Mb defined by D9S1818 (centromeric) and D9SH6 (telomeric). This interval overlaps with the previously reported DFNB33 locus whose chromosomal map position has been recently revised and assigned to a new position on chromosome 10p11.23-q21.1. The Nonsyndromic Deafness locus on chromosome 9q segregating in family PKDF280 was designated DFNB79. We are currently screening the 113 candidate DFNB79 genes for mutations and have excluded CACNA1B, EDF1, PTGDS, EHMT1, QSOX2, NOTCH1, MIR126 and MIR602.
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Gene structure and mutant alleles of PCDH15: Nonsyndromic Deafness DFNB23 and type 1 Usher syndrome
Human Genetics, 2008Co-Authors: Zubair M Ahmed, Saima Riazuddin, Saima Anwar, Sheikh Riazuddin, Hanka Venselaar, Polina P. Belyantseva, Muhammad Qasim, Thomas B FriedmanAbstract:Mutations of PCDH15 , encoding protocadherin 15, can cause either combined hearing and vision impairment (type 1 Usher syndrome; USH1F) or Nonsyndromic Deafness (DFNB23). Human PCDH15 is reported to be composed of 35 exons and encodes a variety of isoforms with 3–11 ectodomains (ECs), a transmembrane domain and a carboxy-terminal cytoplasmic domain (CD). Building on these observations, we describe an updated gene structure that has four additional exons of PCDH15 and isoforms that can be subdivided into four classes. Human PCDH15 encodes three alternative, evolutionarily conserved unique cytoplasmic domains (CD1, CD2 or CD3). Families ascertained on the basis of prelingual hearing loss were screened for linkage of this phenotype to markers for PCDH15 on chromosome 10q21.1. In seven of twelve families segregating USH1, we identified homozygous mutant alleles (one missense, one splice site, three nonsense and two deletion mutations) of which six are novel. One family was segregating Nonsyndromic Deafness DFNB23 due to a homozygous missense mutation. To date, in our cohort of 557 Pakistani families, we have found 11 different PCDH15 mutations that account for Deafness in 13 families. Molecular modeling provided mechanistic insight into the phenotypic variation in severity of the PCDH15 missense mutations. We did not find pathogenic mutations in five of the twelve USH1 families linked to markers for USH1F , which suggest either the presence of mutations of yet additional undiscovered exons of PCDH15 , mutations in the introns or regulatory elements of PCDH15 , or an additional locus for type I USH at chromosome 10q21.1.
Sheikh Riazuddin - One of the best experts on this subject based on the ideXlab platform.
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Nonsyndromic Deafness it ain t necessarily so
2014Co-Authors: Thomas B Friedman, Sheikh RiazuddinAbstract:Hair cells are physiologically and structurally unique. However, the expression of the majority of macromolecules used for development and maintenance of their remarkable complexity appears to have been epigenetically hijacked from other functions during the evolution of the auditory system. The broad expression of many of these purloined genes should suggest caution when assuming that a particular mutated gene is causing simple isolated (Nonsyndromic) hearing loss with no other medically significant features. Medically relevant issues accompanying hearing loss may be overlooked inadvertently. Narrowly focused medical history questions to be asked of study subjects and the selection of specific clinical tests often follow from knowledge of gene function in the various organ systems. These data are usually available only after Deafness gene identification and the study of mouse models that recapitulate the inherited human Deafness, and such studies may take several years. How many of the reported Nonsyndromic Deafness disorders are syndromic, in reality, remains to be determined. Early in a study of hereditary Deafness, this can be an inherently difficult issue to resolve. Therefore, we suggest provisional classification of a specific human hereditary hearing loss as Nonsyndromic only until there is adequate understanding of the normal function and expression pattern of a Deafness gene that can then guide a focused clinical evaluation. This chapter examines these issues.
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dfnb79 reincarnation of a Nonsyndromic Deafness locus on chromosome 9q34 3
European Journal of Human Genetics, 2010Co-Authors: Shahid Y Khan, Saima Riazuddin, Zubair M Ahmed, Ahmad Usman Zafar, Robert J Morell, Atteeq U Rehman, Mohsin Shahzad, Nazir Ahmed, Andrew J. Griffith, Sheikh RiazuddinAbstract:Genetic analysis of an inbred Pakistani family PKDF280, segregating prelingual severe to profound sensorineural hearing loss, provided evidence for a DFNB locus on human chromosome 9q34.3. Co-segregation of the Deafness trait with marker D9SH159 was determined by a two-point linkage analysis (LOD score 9.43 at θ=0). Two additional large families, PKDF517 and PKDF741, co-segregate recessive Deafness with markers linked to the same interval. Haplotype analyses of these three families refined the interval to 3.84 Mb defined by D9S1818 (centromeric) and D9SH6 (telomeric). This interval overlaps with the previously reported DFNB33 locus whose chromosomal map position has been recently revised and assigned to a new position on chromosome 10p11.23–q21.1. The Nonsyndromic Deafness locus on chromosome 9q segregating in family PKDF280 was designated DFNB79. We are currently screening the 113 candidate DFNB79 genes for mutations and have excluded CACNA1B, EDF1, PTGDS, EHMT1, QSOX2, NOTCH1, MIR126 and MIR602.
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Gene structure and mutant alleles of PCDH15: Nonsyndromic Deafness DFNB23 and type 1 Usher syndrome
Human Genetics, 2008Co-Authors: Zubair M Ahmed, Saima Riazuddin, Saima Anwar, Sheikh Riazuddin, Hanka Venselaar, Polina P. Belyantseva, Muhammad Qasim, Thomas B FriedmanAbstract:Mutations of PCDH15 , encoding protocadherin 15, can cause either combined hearing and vision impairment (type 1 Usher syndrome; USH1F) or Nonsyndromic Deafness (DFNB23). Human PCDH15 is reported to be composed of 35 exons and encodes a variety of isoforms with 3–11 ectodomains (ECs), a transmembrane domain and a carboxy-terminal cytoplasmic domain (CD). Building on these observations, we describe an updated gene structure that has four additional exons of PCDH15 and isoforms that can be subdivided into four classes. Human PCDH15 encodes three alternative, evolutionarily conserved unique cytoplasmic domains (CD1, CD2 or CD3). Families ascertained on the basis of prelingual hearing loss were screened for linkage of this phenotype to markers for PCDH15 on chromosome 10q21.1. In seven of twelve families segregating USH1, we identified homozygous mutant alleles (one missense, one splice site, three nonsense and two deletion mutations) of which six are novel. One family was segregating Nonsyndromic Deafness DFNB23 due to a homozygous missense mutation. To date, in our cohort of 557 Pakistani families, we have found 11 different PCDH15 mutations that account for Deafness in 13 families. Molecular modeling provided mechanistic insight into the phenotypic variation in severity of the PCDH15 missense mutations. We did not find pathogenic mutations in five of the twelve USH1 families linked to markers for USH1F , which suggest either the presence of mutations of yet additional undiscovered exons of PCDH15 , mutations in the introns or regulatory elements of PCDH15 , or an additional locus for type I USH at chromosome 10q21.1.
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a new locus for Nonsyndromic Deafness dfnb51 maps to chromosome 11p13 p12
American Journal of Medical Genetics Part A, 2005Co-Authors: Rehan S. Shaikh, Saima Riazuddin, Zubair M Ahmed, Thomas B Friedman, Shaheen N Khan, Khushnooda Ramzan, Sabiha Nazli, Sameera Sattar, Sheikh RiazuddinAbstract:Rehan Sadiq Shaikh, Khushnooda Ramzan, Sabiha Nazli, Sameera Sattar, Shaheen N. Khan, Saima Riazuddin, Zubair M. Ahmed, Thomas B. Friedman, and Sheikh Riazuddin* National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan Section on Human Genetics, Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland
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dfnb48 a new Nonsyndromic recessive Deafness locus maps to chromosome 15q23 q25 1
Human Genetics, 2005Co-Authors: Jamil Ahmad, Saima Riazuddin, Zubair M Ahmed, Shahid Y Khan, Thomas B Friedman, Shaheen N Khan, Khushnooda Ramzan, Edward R. Wilcox, Sheikh RiazuddinAbstract:Nonsyndromic Deafness locus (DFNB48) segregating as an autosomal recessive trait has been mapped to the long arm of chromosome 15 in bands q23-q25.1 in five large Pakistani families. The Deafness phenotype in one of these five families (PKDF245) is linked to D15S1005 with a lod score of 8.6 at θ=0, and there is a critical linkage interval of approximately 7 cM on the Marshfield human genetic map, bounded by microsatellite markers D15S216 (70.73 cM) and D15S1041 (77.69 cM). MYO9A, NR2E3, BBS4, and TMC3 are among the candidate genes in the DFNB48 region. The identification of another novel Nonsyndromic recessive Deafness locus demonstrates the high degree of locus heterogeneity for hearing impairment, particularly in the Pakistani population.
Zubair M Ahmed - One of the best experts on this subject based on the ideXlab platform.
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dfnb79 reincarnation of a Nonsyndromic Deafness locus on chromosome 9q34 3
European Journal of Human Genetics, 2010Co-Authors: Shahid Y Khan, Saima Riazuddin, Zubair M Ahmed, Ahmad Usman Zafar, Robert J Morell, Atteeq U Rehman, Mohsin Shahzad, Nazir Ahmed, Andrew J. Griffith, Sheikh RiazuddinAbstract:Genetic analysis of an inbred Pakistani family PKDF280, segregating prelingual severe to profound sensorineural hearing loss, provided evidence for a DFNB locus on human chromosome 9q34.3. Co-segregation of the Deafness trait with marker D9SH159 was determined by a two-point linkage analysis (LOD score 9.43 at θ=0). Two additional large families, PKDF517 and PKDF741, co-segregate recessive Deafness with markers linked to the same interval. Haplotype analyses of these three families refined the interval to 3.84 Mb defined by D9S1818 (centromeric) and D9SH6 (telomeric). This interval overlaps with the previously reported DFNB33 locus whose chromosomal map position has been recently revised and assigned to a new position on chromosome 10p11.23–q21.1. The Nonsyndromic Deafness locus on chromosome 9q segregating in family PKDF280 was designated DFNB79. We are currently screening the 113 candidate DFNB79 genes for mutations and have excluded CACNA1B, EDF1, PTGDS, EHMT1, QSOX2, NOTCH1, MIR126 and MIR602.
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molecular basis of dfnb73 mutations of bsnd can cause Nonsyndromic Deafness or bartter syndrome
American Journal of Human Genetics, 2009Co-Authors: Saima Riazuddin, Saima Anwar, Martin Fischer, Zubair M Ahmed, Shahid Y Khan, Audrey G H Janssen, Ahmad Usman Zafar, Ute I SchollAbstract:BSND encodes barttin, an accessory subunit of renal and inner ear chloride channels. To date, all mutations of BSND have been shown to cause Bartter syndrome type IV, characterized by significant renal abnormalities and Deafness. We identified a BSND mutation (p.I12T) in four kindreds segregating Nonsyndromic Deafness linked to a 4.04-cM interval on chromosome 1p32.3. The functional consequences of p.I12T differ from BSND mutations that cause renal failure and Deafness in Bartter syndrome type IV. p.I12T leaves chloride channel function unaffected and only interferes with chaperone function of barttin in intracellular trafficking. This study provides functional data implicating a hypomorphic allele of BSND as a cause of apparent Nonsyndromic Deafness. We demonstrate that BSND mutations with different functional consequences are the basis for either syndromic or Nonsyndromic Deafness.
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Gene structure and mutant alleles of PCDH15: Nonsyndromic Deafness DFNB23 and type 1 Usher syndrome
Human Genetics, 2008Co-Authors: Zubair M Ahmed, Saima Riazuddin, Saima Anwar, Sheikh Riazuddin, Hanka Venselaar, Polina P. Belyantseva, Muhammad Qasim, Thomas B FriedmanAbstract:Mutations of PCDH15 , encoding protocadherin 15, can cause either combined hearing and vision impairment (type 1 Usher syndrome; USH1F) or Nonsyndromic Deafness (DFNB23). Human PCDH15 is reported to be composed of 35 exons and encodes a variety of isoforms with 3–11 ectodomains (ECs), a transmembrane domain and a carboxy-terminal cytoplasmic domain (CD). Building on these observations, we describe an updated gene structure that has four additional exons of PCDH15 and isoforms that can be subdivided into four classes. Human PCDH15 encodes three alternative, evolutionarily conserved unique cytoplasmic domains (CD1, CD2 or CD3). Families ascertained on the basis of prelingual hearing loss were screened for linkage of this phenotype to markers for PCDH15 on chromosome 10q21.1. In seven of twelve families segregating USH1, we identified homozygous mutant alleles (one missense, one splice site, three nonsense and two deletion mutations) of which six are novel. One family was segregating Nonsyndromic Deafness DFNB23 due to a homozygous missense mutation. To date, in our cohort of 557 Pakistani families, we have found 11 different PCDH15 mutations that account for Deafness in 13 families. Molecular modeling provided mechanistic insight into the phenotypic variation in severity of the PCDH15 missense mutations. We did not find pathogenic mutations in five of the twelve USH1 families linked to markers for USH1F , which suggest either the presence of mutations of yet additional undiscovered exons of PCDH15 , mutations in the introns or regulatory elements of PCDH15 , or an additional locus for type I USH at chromosome 10q21.1.
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mutation spectrum of myo7a and evaluation of a novel Nonsyndromic Deafness dfnb2 allele with residual function
Human Mutation, 2008Co-Authors: Saima Riazuddin, Zubair M Ahmed, Shaheen N Khan, Rehan S. Shaikh, Sabiha Nazli, Yi Yang, Fareeha Zulfiqar, Ahmed U Zafar, Farooq Sabar, Fouzia T JavidAbstract:Department ofBiology, University of Maryland, College Park, MarylandCommunicated by Dvorah AbeliovichRecessive mutations of MYO7A, encoding unconventional myosin VIIA, can cause either a deaf-blindnesssyndrome (type 1 Usher syndrome; USH1B) or Nonsyndromic Deafness (DFNB2). In our study, Deafnesssegregating as a recessive trait in 24 consanguineous families showed linkage to markers for the DFNB2/USH1B locus on chromosome 11q13.5. A total of 23 of these families segregate USH1 due to 17 homozygousmutant MYO7A alleles, of which 14 are novel. One family segregated Nonsyndromic hearing loss DFNB2 due toa novel three-nucleotide deletion in an exon of MYO7A (p.E1716del) encoding a region of the tail domain. Wehypothesized that DFNB2 alleles of MYO7A have residual myosin VIIA. To address this question weinvestigated the effects of several mutant alleles by making green fluorescent protein (GFP) tagged cDNAexpression constructs containing engineered mutations of mouse Myo7a at codons equivalent to pathogenicUSH1B and DFNB2 alleles of human MYO7A. We show that in transfected mouse hair cells an USH1Bmutant GFP-myosin VIIa does not localize properly to inner ear hair cell stereocilia. However, a GFP-myosinVIIa protein engineered to have an equivalent DFNB2 mutation to p.E1716del localizes correctly in transfectedmouse hair cells. This finding is consistent with the hypothesis that p.E1716del causes a less severe phenotype(DFNB2) than the USH1B-associated alleles because the resulting protein retains some degree of normalfunction. Hum Mutat 0, 1–10, 2008.
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The autosomal recessive Nonsyndromic Deafness locus DFNB72 is located on chromosome 19p13.3
Human Genetics, 2007Co-Authors: Sabiha Nazli, Saima Riazuddin, Zubair M Ahmed, Andrew J. Griffith, Shaheen N Khan, Tayyab Husnain, Ateeq-ul Jaleel, S. Amer Riazuddin, Ahmad U. Zafar, Thomas B FriedmanAbstract:We ascertained three consanguineous Pakistani families (PKDF291, PKDF335 and PKDF793) segregating Nonsyndromic recessive hearing loss. The hearing loss segregating in PKDF335 and PKDF793 is moderate to severe, whereas it is profound in PKDF291. The maximum two-point LOD scores are 3.01 (D19S1034), 3.85 (D19S894) and 3.71 (D19S894) for PKDF291, PKDF335 and PKDF793, respectively. Haplotype analyses of the three families define a 1.16 Mb region of overlap of the homozygous linkage intervals bounded by markers D19S216 (20.01 cM) and D19S1034 (20.75 cM). These results define a novel locus, DFNB72 , on chromosome 19p13.3. There are at least 22 genes in the 1.16 Mb interval, including PTPRS , ZNRF4 and CAPS . We identified no pathogenic variants in the exons and flanking intronic sequences of these three genes in affected members of the DFNB72 families. DFNB72 is telomeric to DFNB68 , the only other known Deafness locus with statistically significant support for linkage to chromosome 19p.
Thomas B Friedman - One of the best experts on this subject based on the ideXlab platform.
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Nonsyndromic Deafness: It Ain’t Necessarily So
Perspectives on Auditory Research, 2020Co-Authors: Thomas B Friedman, RiazuddinAbstract:Hair cells are physiologically and structurally unique. However, the expression of the majority of macromolecules used for development and maintenance of their remarkable complexity appears to have been epigenetically hijacked from other functions during the evolution of the auditory system. The broad expression of many of these purloined genes should suggest caution when assuming that a particular mutated gene is causing simple isolated (Nonsyndromic) hearing loss with no other medically significant features. Medically relevant issues accompanying hearing loss may be overlooked inadvertently. Narrowly focused medical history questions to be asked of study subjects and the selection of specific clinical tests often follow from knowledge of gene function in the various organ systems. These data are usually available only after Deafness gene identification and the study of mouse models that recapitulate the inherited human Deafness, and such studies may take several years. How many of the reported Nonsyndromic Deafness disorders are syndromic, in reality, remains to be determined. Early in a study of hereditary Deafness, this can be an inherently difficult issue to resolve. Therefore, we suggest provisional classification of a specific human hereditary hearing loss as Nonsyndromic only until there is adequate understanding of the normal function and expression pattern of a Deafness gene that can then guide a focused clinical evaluation. This chapter examines these issues.
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Nonsyndromic Deafness it ain t necessarily so
2014Co-Authors: Thomas B Friedman, Sheikh RiazuddinAbstract:Hair cells are physiologically and structurally unique. However, the expression of the majority of macromolecules used for development and maintenance of their remarkable complexity appears to have been epigenetically hijacked from other functions during the evolution of the auditory system. The broad expression of many of these purloined genes should suggest caution when assuming that a particular mutated gene is causing simple isolated (Nonsyndromic) hearing loss with no other medically significant features. Medically relevant issues accompanying hearing loss may be overlooked inadvertently. Narrowly focused medical history questions to be asked of study subjects and the selection of specific clinical tests often follow from knowledge of gene function in the various organ systems. These data are usually available only after Deafness gene identification and the study of mouse models that recapitulate the inherited human Deafness, and such studies may take several years. How many of the reported Nonsyndromic Deafness disorders are syndromic, in reality, remains to be determined. Early in a study of hereditary Deafness, this can be an inherently difficult issue to resolve. Therefore, we suggest provisional classification of a specific human hereditary hearing loss as Nonsyndromic only until there is adequate understanding of the normal function and expression pattern of a Deafness gene that can then guide a focused clinical evaluation. This chapter examines these issues.
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Gene structure and mutant alleles of PCDH15: Nonsyndromic Deafness DFNB23 and type 1 Usher syndrome
Human Genetics, 2008Co-Authors: Zubair M Ahmed, Saima Riazuddin, Saima Anwar, Sheikh Riazuddin, Hanka Venselaar, Polina P. Belyantseva, Muhammad Qasim, Thomas B FriedmanAbstract:Mutations of PCDH15 , encoding protocadherin 15, can cause either combined hearing and vision impairment (type 1 Usher syndrome; USH1F) or Nonsyndromic Deafness (DFNB23). Human PCDH15 is reported to be composed of 35 exons and encodes a variety of isoforms with 3–11 ectodomains (ECs), a transmembrane domain and a carboxy-terminal cytoplasmic domain (CD). Building on these observations, we describe an updated gene structure that has four additional exons of PCDH15 and isoforms that can be subdivided into four classes. Human PCDH15 encodes three alternative, evolutionarily conserved unique cytoplasmic domains (CD1, CD2 or CD3). Families ascertained on the basis of prelingual hearing loss were screened for linkage of this phenotype to markers for PCDH15 on chromosome 10q21.1. In seven of twelve families segregating USH1, we identified homozygous mutant alleles (one missense, one splice site, three nonsense and two deletion mutations) of which six are novel. One family was segregating Nonsyndromic Deafness DFNB23 due to a homozygous missense mutation. To date, in our cohort of 557 Pakistani families, we have found 11 different PCDH15 mutations that account for Deafness in 13 families. Molecular modeling provided mechanistic insight into the phenotypic variation in severity of the PCDH15 missense mutations. We did not find pathogenic mutations in five of the twelve USH1 families linked to markers for USH1F , which suggest either the presence of mutations of yet additional undiscovered exons of PCDH15 , mutations in the introns or regulatory elements of PCDH15 , or an additional locus for type I USH at chromosome 10q21.1.
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The autosomal recessive Nonsyndromic Deafness locus DFNB72 is located on chromosome 19p13.3
Human Genetics, 2007Co-Authors: Sabiha Nazli, Saima Riazuddin, Zubair M Ahmed, Andrew J. Griffith, Shaheen N Khan, Tayyab Husnain, Ateeq-ul Jaleel, S. Amer Riazuddin, Ahmad U. Zafar, Thomas B FriedmanAbstract:We ascertained three consanguineous Pakistani families (PKDF291, PKDF335 and PKDF793) segregating Nonsyndromic recessive hearing loss. The hearing loss segregating in PKDF335 and PKDF793 is moderate to severe, whereas it is profound in PKDF291. The maximum two-point LOD scores are 3.01 (D19S1034), 3.85 (D19S894) and 3.71 (D19S894) for PKDF291, PKDF335 and PKDF793, respectively. Haplotype analyses of the three families define a 1.16 Mb region of overlap of the homozygous linkage intervals bounded by markers D19S216 (20.01 cM) and D19S1034 (20.75 cM). These results define a novel locus, DFNB72 , on chromosome 19p13.3. There are at least 22 genes in the 1.16 Mb interval, including PTPRS , ZNRF4 and CAPS . We identified no pathogenic variants in the exons and flanking intronic sequences of these three genes in affected members of the DFNB72 families. DFNB72 is telomeric to DFNB68 , the only other known Deafness locus with statistically significant support for linkage to chromosome 19p.
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autosomal recessive Nonsyndromic Deafness locus dfnb63 at chromosome 11q13 2 q13 3
Human Genetics, 2007Co-Authors: Shahid Y Khan, Saima Riazuddin, Saima Anwar, Zubair M Ahmed, Muhammad Tariq, Muhammad Imran Shabbir, Amer S Riazuddin, Shaheen N Khan, Tayyab Husnain, Thomas B FriedmanAbstract:A genome wide linkage analysis of Nonsyndromic Deafness segregating in a consanguineous Pakistani family (PKDF537) was used to identify DFNB63, a new locus for congenital profound sensorineural hearing loss. A maximum two-point lod score of 6.98 at θ = 0 was obtained for marker D11S1337 (68.55 cM). Genotyping of 550 families revealed three additional families (PKDF295, PKDF702 and PKDF817) segregating hearing loss linked to chromosome 11q13.2-q13.3. Meiotic recombination events in these four families define a critical interval of 4.81 cM bounded by markers D11S4113 (68.01 cM) and D11S4162 (72.82 cM), and SHANK2, FGF-3, TPCN2 and CTTN are among the candidate genes in this interval. Positional identification of this Deafness gene should reveal a protein necessary for normal development and/or function of the auditory system.
Robert J Morell - One of the best experts on this subject based on the ideXlab platform.
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noncoding microdeletion in mouse hgf disrupts neural crest migration into the stria vascularis reduces the endocochlear potential and suggests the neuropathology for human Nonsyndromic Deafness dfnb39
The Journal of Neuroscience, 2020Co-Authors: Robert J Morell, Rafal Olszewski, Risa Tona, Samuel Leitess, Talah T Wafa, Ian Taukulis, Julie M Schultz, Elizabeth J Thomason, Keri Richards, Brittany N WhitleyAbstract:Hepatocyte growth factor (HGF) is a multifunctional protein that signals through the MET receptor. HGF stimulates cell proliferation, cell dispersion, neuronal survival and wound healing. In the inner ear, levels of HGF must be fine-tuned for normal hearing. In mice, a deficiency of HGF expression limited to the auditory system, or an over-expression of HGF, cause neurosensory Deafness. In humans, noncoding variants in HGF are associated with Nonsyndromic Deafness DFNB39. However, the mechanism by which these noncoding variants causes Deafness was unknown. Here, we reveal the cause of this Deafness using a mouse model engineered with a noncoding intronic 10bp deletion (del10) in Hgf. Male and female mice homozygous for del10 exhibit moderate-to-profound hearing loss at four weeks of age as measured by tone burst auditory brainstem responses (ABRs). The wild type +80 millivolt endocochlear potential (EP) was significantly reduced in homozygous del10 mice compared to wild type littermates. In normal cochlea, EPs are dependent on ion homeostasis mediated by the stria vascularis (SV). Previous studies showed that developmental incorporation of neural crest cells into the SV depends on signaling from HGF/MET. We show by immunohistochemistry that in del10 homozygotes, neural crest cells fail to infiltrate the developing SV intermediate layer. Phenotyping and RNAseq analyses reveal no other significant abnormalities in other tissues. We conclude that, in the inner ear, the noncoding del10 mutation in Hgf leads to developmental defects of the SV and consequently dysfunctional ion homeostasis and, a reduction in the EP, recapitulating human DFNB39 Nonsyndromic Deafness. Significance Statement: Hereditary Deafness is a common, clinically and genetically heterogeneous neurosensory disorder. Previously we reported that human Deafness DFNB39 is associated with noncoding variants in the 3’UTR of a short isoform of HGF encoding hepatocyte growth factor. For normal hearing, HGF levels must be fine-tuned as an excess or deficiency of HGF cause Deafness in mouse. Using a Hgf mutant mouse with a small 10 base pair deletion recapitulating a human DFNB39 noncoding variant, we demonstrate that neural crest cells fail to migrate into the stria vascularis intermediate layer, resulting in a significantly reduced endocochlear potential, the driving force for sound transduction by inner ear hair cells. HGF-associated Deafness is a neurocristopathy but, unlike many other neurocristopathies, it is not syndromic.
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noncoding microdeletion in mouse hgf disrupts neural crest migration into the stria vascularis reduces the endocochlear potential and suggests the neuropathology for human Nonsyndromic Deafness dfnb39
bioRxiv, 2019Co-Authors: Robert J Morell, Rafal Olszewski, Risa Tona, Samuel Leitess, Julie M Schultz, Elizabeth J Thomason, Brittany N Whitley, Connor Hill, Thomas L Saunders, Matthew F StarostAbstract:Abstract Hepatocyte growth factor (HGF) is a multifunctional protein that signals through the MET receptor. HGF stimulates cell proliferation, cell dispersion, neuronal survival and wound healing. In the inner ear, levels of HGF must be fine-tuned for normal hearing. In mouse, a deficiency of HGF expression limited to the auditory system, or over-expression of HGF, cause neurosensory Deafness. In human, noncoding variants in HGF are associated with Nonsyndromic Deafness DFNB39. However, the mechanism by which these noncoding variants causes Deafness was unknown. Here, we reveal the cause of this Deafness using a mouse model engineered with a noncoding intronic 10bp deletion (del10) in Hgf, which is located in the 3’UTR of a conserved short isoform (Hgf/NK0.5). Mice homozygous for del10 exhibit moderate-to-profound hearing loss at four weeks of age as measured by pure-tone auditory brainstem responses (ABRs). The wild type +80 millivolt endocochlear potential (EP) was significantly reduced in homozygous del10 mice compared to wild type littermates. In normal cochlea, EPs are dependent on ion homeostasis mediated by the stria vascularis (SV). Previous studies showed that developmental incorporation of neural crest cells into the SV depends on signaling from HGF/MET. We show by immunohistochemistry that in del10 homozygotes, neural crest cells fail to infiltrate the developing SV intermediate layer. Phenotyping and RNAseq analyses reveal no other significant abnormalities in other tissues. We conclude that, in the inner ear, the noncoding del10 mutation in Hgf leads to dysfunctional ion homeostasis in the SV and a loss of EP, recapitulating human DFNB39 Deafness. Significance Statement Hereditary Deafness is a common, clinically and genetically heterogeneous neurosensory disorder. Previously we reported that human Deafness DFNB39 is associated with noncoding variants in the 3’UTR of a short isoform of HGF encoding hepatocyte growth factor. For normal hearing, HGF levels must be fined-tuned as an excess or deficiency of HGF cause Deafness in mouse. Using a Hgf mutant mouse with a small 10 base pair deletion recapitulating a human DFNB39 noncoding variant, we demonstrate that neural crest cells fail to migrate into the stria vascularis intermediate layer, resulting in a significantly reduced endocochlear potential, the driving force for sound transduction by inner ear hair cells. HGF-associated Deafness is a neurocristopathy but, unlike many other neurocristopathies, it is not syndromic.
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mutations in tbc1d24 a gene associated with epilepsy also cause Nonsyndromic Deafness dfnb86
American Journal of Human Genetics, 2014Co-Authors: Atteeq U Rehman, Robert J Morell, Regie Lyn P Santoscortez, Meghan C Drummond, Asma A Khan, Muhammad Asim Raza Basra, Naveed Wasif, Muhammad Ayub, Syed Irfan Raza, Deborah A NickersonAbstract:Inherited Deafness is clinically and genetically heterogeneous. We recently mapped DFNB86, a locus associated with Nonsyndromic Deafness, to chromosome 16p. In this study, whole-exome sequencing was performed with genomic DNA from affected individuals from three large consanguineous families in which markers linked to DFNB86 segregate with profound Deafness. Analyses of these data revealed homozygous mutation c.208G>T (p.Asp70Tyr) or c.878G>C (p.Arg293Pro) in TBC1D24 as the underlying cause of Deafness in the three families. Sanger sequence analysis of TBC1D24 in an additional large family in which Deafness segregates with DFNB86 identified the c.208G>T (p.Asp70Tyr) substitution. These mutations affect TBC1D24 amino acid residues that are conserved in orthologs ranging from fruit fly to human. Neither variant was observed in databases of single-nucleotide variants or in 634 chromosomes from ethnically matched control subjects. TBC1D24 in the mouse inner ear was immunolocalized predominantly to spiral ganglion neurons, indicating that DFNB86 Deafness might be an auditory neuropathy spectrum disorder. Previously, six recessive mutations in TBC1D24 were reported to cause seizures (hearing loss was not reported) ranging in severity from epilepsy with otherwise normal development to epileptic encephalopathy resulting in childhood death. Two of our four families in which Deafness segregates with mutant alleles of TBC1D24 were available for neurological examination. Cosegregation of epilepsy and Deafness was not observed in these two families. Although the causal relationship between genotype and phenotype is not presently understood, our findings, combined with published data, indicate that recessive alleles of TBC1D24 can cause either epilepsy or Nonsyndromic Deafness.
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dfnb79 reincarnation of a Nonsyndromic Deafness locus on chromosome 9q34 3
European Journal of Human Genetics, 2010Co-Authors: Shahid Y Khan, Saima Riazuddin, Zubair M Ahmed, Ahmad Usman Zafar, Robert J Morell, Atteeq U Rehman, Mohsin Shahzad, Nazir Ahmed, Andrew J. Griffith, Sheikh RiazuddinAbstract:Genetic analysis of an inbred Pakistani family PKDF280, segregating prelingual severe to profound sensorineural hearing loss, provided evidence for a DFNB locus on human chromosome 9q34.3. Co-segregation of the Deafness trait with marker D9SH159 was determined by a two-point linkage analysis (LOD score 9.43 at θ=0). Two additional large families, PKDF517 and PKDF741, co-segregate recessive Deafness with markers linked to the same interval. Haplotype analyses of these three families refined the interval to 3.84 Mb defined by D9S1818 (centromeric) and D9SH6 (telomeric). This interval overlaps with the previously reported DFNB33 locus whose chromosomal map position has been recently revised and assigned to a new position on chromosome 10p11.23–q21.1. The Nonsyndromic Deafness locus on chromosome 9q segregating in family PKDF280 was designated DFNB79. We are currently screening the 113 candidate DFNB79 genes for mutations and have excluded CACNA1B, EDF1, PTGDS, EHMT1, QSOX2, NOTCH1, MIR126 and MIR602.
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DFNB79: reincarnation of a Nonsyndromic Deafness locus on chromosome 9q34.3
European Journal of Human Genetics, 2009Co-Authors: Shahid Y Khan, Saima Riazuddin, Ahmad Usman Zafar, Robert J Morell, Atteeq U Rehman, Mohsin Shahzad, Nazir Ahmed, Andrew J. Griffith, Zubair Ahmed, RiazuddinAbstract:Genetic analysis of an inbred Pakistani family PKDF280, segregating prelingual severe to profound sensorineural hearing loss, provided evidence for a DFNB locus on human chromosome 9q34.3. Co-segregation of the Deafness trait with marker D9SH159 was determined by a two-point linkage analysis (LOD score 9.43 at theta=0). Two additional large families, PKDF517 and PKDF741, co-segregate recessive Deafness with markers linked to the same interval. Haplotype analyses of these three families refined the interval to 3.84 Mb defined by D9S1818 (centromeric) and D9SH6 (telomeric). This interval overlaps with the previously reported DFNB33 locus whose chromosomal map position has been recently revised and assigned to a new position on chromosome 10p11.23-q21.1. The Nonsyndromic Deafness locus on chromosome 9q segregating in family PKDF280 was designated DFNB79. We are currently screening the 113 candidate DFNB79 genes for mutations and have excluded CACNA1B, EDF1, PTGDS, EHMT1, QSOX2, NOTCH1, MIR126 and MIR602.
