29 results on '"Riazuddin, Sheikh"'
Search Results
2. A mutation in ZNF513, a putative regulator of photoreceptor development, causes autosomal-recessive retinitis pigmentosa
- Author
-
Lin Li, Nakaya, Naoki, Chavali, Venkata R.M., Ma, Zhiwei, Xiaodong Jiao, Sieving, Paul A., Riazuddin, Sheikh, Tomarev, Stanislav I., Ayyagari, Radha, Riazuddin, S. Amer, and Hejtmancik, Fielding J.
- Subjects
Gene expression -- Analysis ,Gene mutations -- Analysis ,In situ hybridization -- Usage ,Photoreceptors -- Genetic aspects ,Retinitis pigmentosa -- Genetic aspects ,Retinitis pigmentosa -- Physiological aspects ,Biological sciences - Abstract
In situ hybridization analysis was used to localize expression of ZNF513 mRNA in the human retina resulting from a homozygous missense mutation and causing autosomal-recessive RP (arRP) or night blindness. The ZNF513 p.C339R mutation is observed to be responsible for RP and ZNF513 plays a key role in the regulation of photoreceptor-specific genes in retinal development and photoreceptor maintenance.
- Published
- 2010
3. A splice-site mutation in a retina-specific exon of BBS8 causes nonsyndromic retinitis pigmentosa
- Author
-
Riazuddin, S. Amer, Iqbal, Muhammad, Yue Wang, Masuda, Tomohiro, Yuhng Chen, Bowne, Sara, Sullivan, Lori S., Waseem, Naushin H., Bhattacharya, Shomi, Daiger, Stephen P., Kang Zhang, Khan, Shaheen N., Riazuddin, Sheikh, Hejtmancik, J. Fielding, Sieving, Paul A., Zack, Donald J., and Katsanis, Nicholas
- Subjects
Bardet-Biedl syndrome -- Causes of ,Bardet-Biedl syndrome -- Genetic aspects ,Pakistanis -- Genetic aspects ,Pakistanis -- Health aspects ,Gene expression -- Analysis ,Biological sciences - Abstract
A splice-site mutation in an unknown exon of BBS8 (MIM 608132), one of the genes involved in pleiotropic Bardet-Biedi syndrome (BBS) which is to cause nonsyndromic recessive RP in a consanguineous Pakistani family is reported. The exon which represented the major BBS8 mRNA species in the mammalian photoreceptor indicated that the encoded 10 amino acids play a pivotal role in the function of BBS8 in retina.
- Published
- 2010
4. Targeted capture and next-generation sequencing identifies C9orf75, encoding taperin, as the mutated gene in nonsyndromic deafness DFNB79
- Author
-
Ur Rehman, Atteeq, Morell, Robert J., Belyantseva, Inna A., Khan, Shahid Y., Boger, Erich T., Shahzad, Mohsin, Ahmed, Zubair M., Riazuddin, Saima, Khan, Shaheen N., Riazuddin, Sheikh, and Friedman, Thomas B.
- Subjects
Nucleotide sequence -- Research ,Deafness -- Genetic aspects ,Deafness -- Research ,Gene mutations -- Research ,Biological sciences - Abstract
A study uses targeted capture and next-generation sequencing to identify the gene which causes nonsyndromic deafness DFNB79. Results reveal that a nonsense mutation in the gene C9orf75, also called TPRN, which encodes the protein taperin, is responsible for the nonsyndromic deafness DFNB79.
- Published
- 2010
5. Molecular basis of DFNB73: mutations of BSND can cause nonsyndromic deafness or Bartter syndrome
- Author
-
Riazuddin, Saima, Anwar, Saima, Fischer, Martin, Ahmed, Zubair M., Khan, Shahid Y., Janssen, Audrey G.H., Zafar, Ahmad U., Scholl, Ute, Husnain, Tayyab, Belyantseva, Inna A., Friedman, Penelope L., Riazuddin, Sheikh, Friedman, Thomas B., and Fahlke, Christoph
- Subjects
Deafness -- Genetic aspects ,Gene mutations -- Analysis ,Human genome -- Research ,Hyperaldosteronism -- Genetic aspects ,Biological sciences - Abstract
A study analyzes the molecular basis of DFNB73 in order to investigate BSND gene mutations that cause Bartter syndrome type IV, characterized by severe renal abnormalities and deafness. Experiments identify a BSND mutation (p.I12T) which selectively affects barttin functioning and causes nonsyndromic deafness, thereby highlighting that different types of BSND mutations can cause syndromic or nonsyndromic deafness in people with Bartter syndrome.
- Published
- 2009
6. Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment of DFNB35
- Author
-
Collin, Rob W.J., Kalay, Ersan, Tariq, Muhammad, Peters, Theo, Zwaag, Bert van der, Venselaar, Hanka, Oostrik, Jaap, Lee, Kwanghyuk, Ahmed, Zubair M., Caylan, Refik, Yun Li, Spierenburg, Henk A., Eyupoglu, Erol, Heister, Angelien, Riazuddin, Saima, Bahat, Elif, Ansar, Muhammad, Arslan, Selcuk, Wollnik, Bernd, Brunner, Han G., Cremers, Cor W.R.J., Karaguzel, Ahmet, Ahmad, Wasim, Cremers, Frans P.M., Vriend, Gert, Friedman, Thomas B., Riazuddin, Sheikh, Leal, Suzanne M., and Kremer, Hannie
- Subjects
Hearing disorders -- Genetic aspects ,Consanguinity -- Health aspects ,Gene mutations -- Health aspects ,Biological sciences - Abstract
The mapping of autosomal-recessive nonsyndromic hearing impairment segregated in a large consanguineous family of Turkish origin to chromosome 14q24.3-q34.12 is described. It is indicated that ESRRB is essential for inner-ear development and function.
- Published
- 2008
7. Tricellulin is a tight-junction protein necessary for hearing
- Author
-
Riazuddin, Saima, Ahmed, Zubair M., Fanning, Alan S., Lagziel, Ayala, Kitajiri, Shin-ichiro, Ramzan, Khusnooda, Khan, Shaheen N., Chattaraj, Parna, Friedman, Penelope L., Anderson, James M., Belyantseva, Inna A., Forge, Andrew, Riazuddin, Sheikh, and Friedman, Thomas B.
- Subjects
Hearing disorders -- Genetic aspects ,Epithelial cells -- Structure ,Epithelial cells -- Research ,Protein folding -- Research ,Biological sciences - Abstract
Tricellulin is concentrated in the tight-type tight junctions (TJs) of mammalian inner-ear epithelia, including the tricellular junctions of the reticular lamina of the organ of Corti. It is also demonstrated that there are multiple alternatively spliced isoforms of TRIC in various tissues and that mutations of TRIC associated with hearing loss remove most of a conserved region in the cytosolic domain that binds to the cytosolic scaffolding protein ZO-1.
- Published
- 2006
8. Mutations in TRIOBP, which encodes a putative cytoskeletal-organizing protein, are associated with nonsyndromic recessive deafness
- Author
-
Riazuddin, Saima, Khan, Shaheen N., Ahmed, Zubair M., Gosh, Manju, Caution, Kyle, Nazli, Sabiha, Kabra, Madhulika, Zafar, Ahmad U., Chen, Kevin, Naz, Sadaf, Antonellis, Anthony, Pavan, William J., Green, Eric D., Wilcox, Edward R., Friedman, Penelope L., Morell, Robert J., Riazuddin, Sheikh, and Friedman, Thomas B.
- Subjects
United States. National Institutes of Health ,Allelomorphism -- Research ,Genetic markers -- Research ,Gene mutations -- Research ,Biological sciences - Published
- 2006
9. Genomewide significant linkage to stuttering on chromosome 12
- Author
-
Riaz, Naveeda, Steinberg, Stacy, Ahmad, Jamil, Pluzhnikov, Anna, Riazuddin, Sheikh, Cox, Nancy J., and Drayna, Dennis
- Subjects
Stuttering ,Biological sciences - Published
- 2005
10. Mutations of MYO6 are associated with recessive deafness, DFNB37. (Report)
- Author
-
Ahmed, Zubair M., Morell, Robert J., Riazuddin, Saima, Gropman, Andrea, Shaukat, Shahzad, Ahmad, Mussaber M., Mohiddin, Saidi A., Fananapazir, Lameh, Caruso, Rafael C., Husnain, Tayyab, Khan, Shaheen N., Riazuddin, Sheikh, Griffith, Andrew J., Friedman, Thomas B., and Wilcox, Edward R.
- Subjects
Gene mutations -- Physiological aspects ,Deafness -- Genetic aspects ,Human genetics -- Research ,Biological sciences - Published
- 2003
11. Mutations in a novel gene, TMIE, are associated with hearing loss linked to the DFNB6 locus. (Report)
- Author
-
Naz, Sadaf, Giguere, Chantal M., Kohrman, David C., Mitchem, Kristina L., Riazuddin, Saima, Morell, Robert J., Ramesh, Arabandi, Srisailpathy, Srikumari, Deshmukh, Dilip, Riazuddin, Sheikh, Griffith, Andrew J., Friedman, Thomas B., Smith, Richard J.H., and Wilcox, Edward R.
- Subjects
Human genetics -- Research ,Gene mutations -- Analysis ,Hearing loss -- Genetic aspects ,Biological sciences - Published
- 2002
12. Mutations of the Protocadherin Gene PCDH15 Cause Usher Syndrome Type 1F
- Author
-
Ahmed, Zubair M., Riazuddin, Saima, Bernstein, Steve L., Ahmed, Zahoor, Khan, Shaheen, Griffith, Andrew J., Morell, Robert J., Friedman, Thomas B., Riazuddin, Sheikh, and Wilcox, Edward R.
- Subjects
Usher's syndrome -- Causes of ,Myosin -- Genetic aspects ,Chromosomes -- Physiological aspects ,Biological sciences - Published
- 2001
13. Usher Syndrome 1D and Nonsyndromic Autosomal Recessive Deafness DFNB12 Are Caused by Allelic Mutations of the Novel Cadherin-Like Gene CDH23
- Author
-
Bork, Julie M., Peters, Linda M., Riazuddin, Saima, Bernstein, Steve L., Ahmed, Zubair M., Ness, Seth L., Polomeno, Robert, Ramesh, Arabandi, Schloss, Melvin, Srisailpathy, C. R. Srikumari, Wayne, Sigrid, Bellman, Susan, Desmukh, Dilip, Ahmed, Zahoor, Khan, Shaheen N., Der Kaloustian, Vazken M., Li, X. Cindy, Lalwani, Anil, Riazuddin, Sheikh, Bitner-Glindzicz, Maria, Nance, Walter E., Liu, Xue-Zhong, Wistow, Graeme, Smith, Richard J. H., Griffith, Andrew J., Wilcox, Edward R., Friedman, Thomas B., and Morell, Robert J.
- Subjects
Usher's syndrome -- Genetic aspects ,Gene mutations -- Physiological aspects ,Deafness -- Genetic aspects ,Retinitis pigmentosa -- Genetic aspects ,Vestibular apparatus -- Diseases ,Biological sciences - Published
- 2001
14. Bi-allelic Variants in METTL5 Cause Autosomal-Recessive Intellectual Disability and Microcephaly.
- Author
-
Richard, Elodie M., Polla, Daniel L., Assir, Muhammad Zaman, Contreras, Minerva, Shahzad, Mohsin, Khan, Asma A., Razzaq, Attia, Akram, Javed, Tarar, Moazzam N., Blanpied, Thomas A., Ahmed, Zubair M., Abou Jamra, Rami, Wieczorek, Dagmar, van Bokhoven, Hans, Riazuddin, Sheikh, and Riazuddin, Saima
- Subjects
- *
INTELLECTUAL disabilities , *HUMAN phenotype , *ADAPTABILITY (Personality) , *FACIAL abnormalities , *BRAIN proteins , *SYNAPSES - Abstract
Intellectual disability (ID) is a genetically and clinically heterogeneous disorder, characterized by limited cognitive abilities and impaired adaptive behaviors. In recent years, exome sequencing (ES) has been instrumental in deciphering the genetic etiology of ID. Here, through ES of a large cohort of individuals with ID, we identified two bi-allelic frameshift variants in METTL5 , c.344_345delGA (p.Arg115Asnfs∗19) and c.571_572delAA (p.Lys191Valfs∗10), in families of Pakistani and Yemenite origin. Both of these variants were segregating with moderate to severe ID, microcephaly, and various facial dysmorphisms, in an autosomal-recessive fashion. METTL5 is a member of the methyltransferase-like protein family, which encompasses proteins with a seven-beta-strand methyltransferase domain. We found METTL5 expression in various substructures of rodent and human brains and METTL5 protein to be enriched in the nucleus and synapses of the hippocampal neurons. Functional studies of these truncating variants in transiently transfected orthologous cells and cultured hippocampal rat neurons revealed no effect on the localization of METTL5 but alter its level of expression. Our in silico analysis and 3D modeling simulation predict disruption of METTL5 function by both variants. Finally, mettl5 knockdown in zebrafish resulted in microcephaly, recapitulating the human phenotype. This study provides evidence that biallelic variants in METTL5 cause ID and microcephaly in humans and highlights the essential role of METTL5 in brain development and neuronal function. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
15. Association between Rare Variants in AP4E1, a Component of Intracellular Trafficking, and Persistent Stuttering.
- Author
-
Raza, M. Hashim, Mattera, Rafael, Morell, Robert, Sainz, Eduardo, Rahn, Rachel, Gutierrez, Joanne, Paris, Emily, Root, Jessica, Solomon, Beth, Brewer, Carmen, Basra, M. Asim Raza, Khan, Shaheen, Riazuddin, Sheikh, Braun, Allen, Bonifacino, Juan S., and Drayna, Dennis
- Subjects
- *
HUMAN genetic variation , *STUTTERERS , *MANNOSE 6-phosphate , *CELLULAR signal transduction , *GENETIC code - Abstract
Stuttering is a common, highly heritable neurodevelopmental disorder characterized by deficits in the volitional control of speech. Whole-exome sequencing identified two heterozygous AP4E1 coding variants, c.1549G>A (p.Val517Ile) and c.2401G>A (p.Glu801Lys), that co-segregate with persistent developmental stuttering in a large Cameroonian family, and we observed the same two variants in unrelated Cameroonians with persistent stuttering. We found 23 other rare variants, including predicted loss-of-function variants, in AP4E1 in unrelated stuttering individuals in Cameroon, Pakistan, and North America. The rate of rare variants in AP4E1 was significantly higher in unrelated Pakistani and Cameroonian stuttering individuals than in population-matched control individuals, and coding variants in this gene are exceptionally rare in the general sub-Saharan West African, South Asian, and North American populations. Clinical examination of the Cameroonian family members failed to identify any symptoms previously reported in rare individuals carrying homozygous loss-of-function mutations in this gene. AP4E1 encodes the ε subunit of the heterotetrameric (ε-β4-μ4-σ4) AP-4 complex, involved in protein sorting at the trans -Golgi network. We found that the μ4 subunit of AP-4 interacts with NAGPA, an enzyme involved in the synthesis of the mannose 6-phosphate signal that targets acid hydrolases to the lysosome and the product of a gene previously associated with stuttering. These findings implicate deficits in intracellular trafficking in persistent stuttering. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
16. Mutations in FYCO1 Cause Autosomal-Recessive Congenital Cataracts
- Author
-
Chen, Jianjun, Ma, Zhiwei, Jiao, Xiaodong, Fariss, Robert, Kantorow, Wanda Lee, Kantorow, Marc, Pras, Eran, Frydman, Moshe, Pras, Elon, Riazuddin, Sheikh, Riazuddin, S. Amer, and Hejtmancik, J. Fielding
- Subjects
- *
CATARACT , *GENETIC disorders , *GENETIC mutation , *INFANT diseases , *CRYSTALLINE lens diseases , *CARRIER proteins , *PAKISTANIS , *GENETICS , *DISEASES - Abstract
Congenital cataracts (CCs), responsible for about one-third of blindness in infants, are a major cause of vision loss in children worldwide. Autosomal-recessive congenital cataracts (arCC) form a clinically diverse and genetically heterogeneous group of disorders of the crystalline lens. To identify the genetic cause of arCC in consanguineous Pakistani families, we performed genome-wide linkage analysis and fine mapping and identified linkage to 3p21-p22 with a summed LOD score of 33.42. Mutations in the gene encoding FYVE and coiled-coil domain containing 1 (FYCO1), a PI(3)P-binding protein family member that is associated with the exterior of autophagosomes and mediates microtubule plus-end-directed vesicle transport, were identified in 12 Pakistani families and one Arab Israeli family in which arCC had previously been mapped to the overlapping CATC2 region. Nine different mutations were identified, including c.3755 delC (p.Ala1252AspfsX71), c.3858_3862dupGGAAT (p.Leu1288TrpfsX37), c.1045 C>T (p.Gln349X), c.2206C>T (p.Gln736X), c.2761C>T (p.Arg921X), c.2830C>T (p.Arg944X), c.3150+1 G>T, c.4127T>C (p.Leu1376Pro), and c.1546C>T (p.Gln516X). Fyco1 is expressed in the mouse embryonic and adult lens and peaks at P12d. Expressed mutant proteins p.Leu1288TrpfsX37 and p.Gln736X are truncated on immunoblots. Wild-type and p.L1376P FYCO1, the only missense mutant identified, migrate at the expected molecular mass. Both wild-type and p. Leu1376Pro FYCO1 proteins expressed in human lens epithelial cells partially colocalize to microtubules and are found adjacent to Golgi, but they primarily colocalize to autophagosomes. Thus, FYCO1 is involved in lens development and transparency in humans, and mutations in this gene are one of the most common causes of arCC in the Pakistani population. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
17. Functional Null Mutations of MSRB3 Encoding Methionine Sulfoxide Reductase Are Associated with Human Deafness DFNB74
- Author
-
Ahmed, Zubair M., Yousaf, Rizwan, Lee, Byung Cheon, Khan, Shaheen N., Lee, Sue, Lee, Kwanghyuk, Husnain, Tayyab, Rehman, Atteeq Ur, Bonneux, Sarah, Ansar, Muhammad, Ahmad, Wasim, Leal, Suzanne M., Gladyshev, Vadim N., Belyantseva, Inna A., Van Camp, Guy, Riazuddin, Sheikh, Friedman, Thomas B., and Riazuddin, Saima
- Subjects
- *
NULL mutation , *METHIONINE sulfoxide reductase , *DEAFNESS , *CHROMOSOMES , *CONSANGUINITY , *EXONS (Genetics) - Abstract
The DFNB74 locus for autosomal-recessive, nonsyndromic deafness segregating in three families was previously mapped to a 5.36 Mb interval on chromosome 12q14.2-q15. Subsequently, we ascertained five additional consanguineous families in which deafness segregated with markers at this locus and refined the critical interval to 2.31 Mb. We then sequenced the protein-coding exons of 18 genes in this interval. The affected individuals of six apparently unrelated families were homozygous for the same transversion (c.265T>G) in MSRB3, which encodes a zinc-containing methionine sulfoxide reductase B3. c.265T>G results in a substitution of glycine for cysteine (p.Cys89Gly), and this substitution cosegregates with deafness in the six DFNB74 families. This cysteine residue of MSRB3 is conserved in orthologs from yeast to humans and is involved in binding structural zinc. In vitro, p.Cys89Gly abolished zinc binding and MSRB3 enzymatic activity, indicating that p.Cys89Gly is a loss-of-function allele. The affected individuals in two other families were homozygous for a transition mutation (c.55T>C), which results in a nonsense mutation (p.Arg19X) in alternatively spliced exon 3, encoding a mitochondrial localization signal. This finding suggests that DFNB74 deafness is due to a mitochondrial dysfunction. In a cohort of 1,040 individuals (aged 53–67 years) of European ancestry, we found no association between 17 tagSNPs for MSRB3 and age-related hearing loss. Mouse Msrb3 is expressed widely. In the inner ear, it is found in the sensory epithelium of the organ of Corti and vestibular end organs as well as in cells of the spiral ganglion. Taken together, MSRB3-catalyzed reduction of methionine sulfoxides to methionine is essential for hearing. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
18. A Mutation in ZNF513, a Putative Regulator of Photoreceptor Development, Causes Autosomal-Recessive Retinitis Pigmentosa
- Author
-
Li, Lin, Nakaya, Naoki, Chavali, Venkata R.M., Ma, Zhiwei, Jiao, Xiaodong, Sieving, Paul A., Riazuddin, Sheikh, Tomarev, Stanislav I., Ayyagari, Radha, Riazuddin, S. Amer, and Hejtmancik, J. Fielding
- Subjects
- *
GENETIC mutation , *ZINC-finger proteins , *PHOTORECEPTORS , *RETINITIS pigmentosa , *RETINAL degeneration , *NIGHT blindness , *TRANSCRIPTION factors - Abstract
Retinitis pigmentosa (RP) is a phenotypically and genetically heterogeneous group of inherited retinal degenerations characterized clinically by night blindness, progressive constriction of the visual fields, and loss of vision, and pathologically by progressive loss of rod and then cone photoreceptors. Autosomal-recessive RP (arRP) in a consanguineous Pakistani family previously linked to chromosome 2p22.3-p24.1 is shown to result from a homozygous missense mutation (c.1015T>C [p.C339R]) in ZNF513, encoding a presumptive transcription factor. znf513 is expressed in the retina, especially in the outer nuclear layer, inner nuclear layer, and photoreceptors. Knockdown of znf513 in zebrafish reduces eye size, retinal thickness, and expression of rod and cone opsins and causes specific loss of photoreceptors. These effects are rescued by coinjection with wild-type (WT) but not p.C339R-znf513 mRNA. Both normal and p.C339R mutant ZNF513 proteins expressed in COS-7 cells localize to the nucleus. ChIP analysis shows that only the wild-type but not the mutant ZNF513 binds to the Pax6, Sp4, Arr3, Irbp, and photoreceptor opsin promoters. These results suggest that the ZNF513 p.C339R mutation is responsible for RP in this family and that ZNF513 plays a key role in the regulation of photoreceptor-specific genes in retinal development and photoreceptor maintenance. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
19. Targeted Capture and Next-Generation Sequencing Identifies C9orf75, Encoding Taperin, as the Mutated Gene in Nonsyndromic Deafness DFNB79
- Author
-
Rehman, Atteeq Ur, Morell, Robert J., Belyantseva, Inna A., Khan, Shahid Y., Boger, Erich T., Shahzad, Mohsin, Ahmed, Zubair M., Riazuddin, Saima, Khan, Shaheen N., Riazuddin, Sheikh, and Friedman, Thomas B.
- Subjects
- *
GENETICS of deafness , *HAIR cells , *NUCLEOTIDE sequence , *LOCUS (Genetics) , *GENOMES , *HUMAN genes , *GENETIC mutation - Abstract
Targeted genome capture combined with next-generation sequencing was used to analyze 2.9 Mb of the DFNB79 interval on chromosome 9q34.3, which includes 108 candidate genes. Genomic DNA from an affected member of a consanguineous family segregating recessive, nonsyndromic hearing loss was used to make a library of fragments covering the DFNB79 linkage interval defined by genetic analyses of four pedigrees. Homozygosity for eight previously unreported variants in transcribed sequences was detected by evaluating a library of 402,554 sequencing reads and was later confirmed by Sanger sequencing. Of these variants, six were determined to be polymorphisms in the Pakistani population, and one was in a noncoding gene that was subsequently excluded genetically from the DFNB79 linkage interval. The remaining variant was a nonsense mutation in a predicted gene, C9orf75, renamed TPRN. Evaluation of the other three DFNB79-linked families identified three additional frameshift mutations, for a total of four truncating alleles of this gene. Although TPRN is expressed in many tissues, immunolocalization of the protein product in the mouse cochlea shows prominent expression in the taper region of hair cell stereocilia. Consequently, we named the protein taperin. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
20. De novo and bi-allelic variants in AP1G1 cause neurodevelopmental disorder with developmental delay, intellectual disability, and epilepsy.
- Author
-
Usmani MA, Ahmed ZM, Magini P, Pienkowski VM, Rasmussen KJ, Hernan R, Rasheed F, Hussain M, Shahzad M, Lanpher BC, Niu Z, Lim FY, Pippucci T, Ploski R, Kraus V, Matuszewska K, Palombo F, Kianmahd J, Martinez-Agosto JA, Lee H, Colao E, Motazacker MM, Brigatti KW, Puffenberger EG, Riazuddin SA, Gonzaga-Jauregui C, Chung WK, Wagner M, Schultz MJ, Seri M, Kievit AJA, Perrotti N, Wassink-Ruiter JSK, van Bokhoven H, Riazuddin S, and Riazuddin S
- Subjects
- Alleles, Animals, DNA Mutational Analysis, Female, HEK293 Cells, Humans, Male, Pedigree, Rats, Zebrafish genetics, Adaptor Protein Complex 1 genetics, Developmental Disabilities genetics, Epilepsy genetics, Intellectual Disability genetics, Neurodevelopmental Disorders genetics
- Abstract
Adaptor protein (AP) complexes mediate selective intracellular vesicular trafficking and polarized localization of somatodendritic proteins in neurons. Disease-causing alleles of various subunits of AP complexes have been implicated in several heritable human disorders, including intellectual disabilities (IDs). Here, we report two bi-allelic (c.737C>A [p.Pro246His] and c.1105A>G [p.Met369Val]) and eight de novo heterozygous variants (c.44G>A [p.Arg15Gln], c.103C>T [p.Arg35Trp], c.104G>A [p.Arg35Gln], c.229delC [p.Gln77Lys
∗ 11], c.399_400del [p.Glu133Aspfs∗ 37], c.747G>T [p.Gln249His], c.928-2A>C [p.?], and c.2459C>G [p.Pro820Arg]) in AP1G1, encoding gamma-1 subunit of adaptor-related protein complex 1 (AP1γ1), associated with a neurodevelopmental disorder (NDD) characterized by mild to severe ID, epilepsy, and developmental delay in eleven families from different ethnicities. The AP1γ1-mediated adaptor complex is essential for the formation of clathrin-coated intracellular vesicles. In silico analysis and 3D protein modeling simulation predicted alteration of AP1γ1 protein folding for missense variants, which was consistent with the observed altered AP1γ1 levels in heterologous cells. Functional studies of the recessively inherited missense variants revealed no apparent impact on the interaction of AP1γ1 with other subunits of the AP-1 complex but rather showed to affect the endosome recycling pathway. Knocking out ap1g1 in zebrafish leads to severe morphological defect and lethality, which was significantly rescued by injection of wild-type AP1G1 mRNA and not by transcripts encoding the missense variants. Furthermore, microinjection of mRNAs with de novo missense variants in wild-type zebrafish resulted in severe developmental abnormalities and increased lethality. We conclude that de novo and bi-allelic variants in AP1G1 are associated with neurodevelopmental disorder in diverse populations., (Published by Elsevier Inc.)- Published
- 2021
- Full Text
- View/download PDF
21. Variants in PUS7 Cause Intellectual Disability with Speech Delay, Microcephaly, Short Stature, and Aggressive Behavior.
- Author
-
de Brouwer APM, Abou Jamra R, Körtel N, Soyris C, Polla DL, Safra M, Zisso A, Powell CA, Rebelo-Guiomar P, Dinges N, Morin V, Stock M, Hussain M, Shahzad M, Riazuddin S, Ahmed ZM, Pfundt R, Schwarz F, de Boer L, Reis A, Grozeva D, Raymond FL, Riazuddin S, Koolen DA, Minczuk M, Roignant JY, van Bokhoven H, and Schwartz S
- Subjects
- Adolescent, Animals, Child, Drosophila melanogaster genetics, Exons genetics, Female, Gene Knockout Techniques methods, Homozygote, Humans, Male, Pedigree, Phenotype, RNA, Messenger genetics, RNA, Transfer genetics, Aggression physiology, Dwarfism genetics, Genetic Variation genetics, Intellectual Disability genetics, Language Development Disorders genetics, Microcephaly genetics
- Abstract
We describe six persons from three families with three homozygous protein truncating variants in PUS7: c.89_90del (p.Thr30Lysfs
∗ 20), c.1348C>T (p.Arg450∗ ), and a deletion of the penultimate exon 15. All these individuals have intellectual disability with speech delay, short stature, microcephaly, and aggressive behavior. PUS7 encodes the RNA-independent pseudouridylate synthase 7. Pseudouridylation is the most abundant post-transcriptional modification in RNA, which is primarily thought to stabilize secondary structures of RNA. We show that the disease-related variants lead to abolishment of PUS7 activity on both tRNA and mRNA substrates. Moreover, pus7 knockout in Drosophila melanogaster results in a number of behavioral defects, including increased activity, disorientation, and aggressiveness supporting that neurological defects are caused by PUS7 variants. Our findings demonstrate that RNA pseudouridylation by PUS7 is essential for proper neuronal development and function., (Copyright © 2018 American Society of Human Genetics. All rights reserved.)- Published
- 2018
- Full Text
- View/download PDF
22. Homozygous Truncating Variants in TBC1D23 Cause Pontocerebellar Hypoplasia and Alter Cortical Development.
- Author
-
Ivanova EL, Mau-Them FT, Riazuddin S, Kahrizi K, Laugel V, Schaefer E, de Saint Martin A, Runge K, Iqbal Z, Spitz MA, Laura M, Drouot N, Gérard B, Deleuze JF, de Brouwer APM, Razzaq A, Dollfus H, Assir MZ, Nitchké P, Hinckelmann MV, Ropers H, Riazuddin S, Najmabadi H, van Bokhoven H, and Chelly J
- Subjects
- Adolescent, Animals, Cells, Cultured, Cerebellar Diseases pathology, Cerebellum pathology, Child, Child, Preschool, Developmental Disabilities genetics, Developmental Disabilities pathology, Embryo, Mammalian metabolism, Embryo, Mammalian pathology, Female, Humans, Intellectual Disability genetics, Intellectual Disability pathology, Male, Mice, Microcephaly pathology, Nervous System Malformations pathology, Neuroblastoma genetics, Neuroblastoma pathology, Neuronal Outgrowth, Neurons metabolism, Pedigree, Cerebellar Diseases genetics, Cerebellum abnormalities, GTPase-Activating Proteins genetics, Homozygote, Microcephaly genetics, Mutation, Nervous System Malformations genetics, Neurons pathology
- Abstract
Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare recessive disorders with prenatal onset, characterized by hypoplasia of pons and cerebellum. Mutations in a small number of genes have been reported to cause PCH, and the vast majority of PCH cases are explained by mutations in TSEN54, which encodes a subunit of the tRNA splicing endonuclease complex. Here we report three families with homozygous truncating mutations in TBC1D23 who display moderate to severe intellectual disability and microcephaly. MRI data from available affected subjects revealed PCH, small normally proportioned cerebellum, and corpus callosum anomalies. Furthermore, through in utero electroporation, we show that downregulation of TBC1D23 affects cortical neuron positioning. TBC1D23 is a member of the Tre2-Bub2-Cdc16 (TBC) domain-containing RAB-specific GTPase-activating proteins (TBC/RABGAPs). Members of this protein family negatively regulate RAB proteins and modulate the signaling between RABs and other small GTPases, some of which have a crucial role in the trafficking of intracellular vesicles and are involved in neurological disorders. Here, we demonstrate that dense core vesicles and lysosomal trafficking dynamics are affected in fibroblasts harboring TBC1D23 mutation. We propose that mutations in TBC1D23 are responsible for a form of PCH with small, normally proportioned cerebellum and should be screened in individuals with syndromic pontocereballar hypoplasia., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
23. Autosomal-Recessive Hearing Impairment Due to Rare Missense Variants within S1PR2.
- Author
-
Santos-Cortez RL, Faridi R, Rehman AU, Lee K, Ansar M, Wang X, Morell RJ, Isaacson R, Belyantseva IA, Dai H, Acharya A, Qaiser TA, Muhammad D, Ali RA, Shams S, Hassan MJ, Shahzad S, Raza SI, Bashir ZE, Smith JD, Nickerson DA, Bamshad MJ, Riazuddin S, Ahmad W, Friedman TB, and Leal SM
- Subjects
- Amino Acid Sequence, Asian People genetics, Chromosomes, Human, Pair 19 genetics, Chromosomes, Human, Pair 19 metabolism, Exome, Hearing Loss diagnosis, Humans, Lod Score, Logistic Models, Lysophospholipids genetics, Lysophospholipids metabolism, Models, Molecular, Molecular Sequence Data, Mutation, Missense, Pedigree, Phenotype, Receptors, Lysosphingolipid metabolism, Sphingosine analogs & derivatives, Sphingosine genetics, Sphingosine metabolism, Sphingosine-1-Phosphate Receptors, Genes, Recessive, Hearing Loss genetics, Receptors, Lysosphingolipid genetics
- Abstract
The sphingosine-1-phosphate receptors (S1PRs) are a well-studied class of transmembrane G protein-coupled sphingolipid receptors that mediate multiple cellular processes. However, S1PRs have not been previously reported to be involved in the genetic etiology of human traits. S1PR2 lies within the autosomal-recessive nonsyndromic hearing impairment (ARNSHI) locus DFNB68 on 19p13.2. From exome sequence data we identified two pathogenic S1PR2 variants, c.323G>C (p.Arg108Pro) and c.419A>G (p.Tyr140Cys). Each of these variants co-segregates with congenital profound hearing impairment in consanguineous Pakistani families with maximum LOD scores of 6.4 for family DEM4154 and 3.3 for family PKDF1400. Neither S1PR2 missense variant was reported among ∼120,000 chromosomes in the Exome Aggregation Consortium database, in 76 unrelated Pakistani exomes, or in 720 Pakistani control chromosomes. Both DNA variants affect highly conserved residues of S1PR2 and are predicted to be damaging by multiple bioinformatics tools. Molecular modeling predicts that these variants affect binding of sphingosine-1-phosphate (p.Arg108Pro) and G protein docking (p.Tyr140Cys). In the previously reported S1pr2(-/-) mice, stria vascularis abnormalities, organ of Corti degeneration, and profound hearing loss were observed. Additionally, hair cell defects were seen in both knockout mice and morphant zebrafish. Family PKDF1400 presents with ARNSHI, which is consistent with the lack of gross malformations in S1pr2(-/-) mice, whereas family DEM4154 has lower limb malformations in addition to hearing loss. Our findings suggest the possibility of developing therapies against hair cell damage (e.g., from ototoxic drugs) through targeted stimulation of S1PR2., (Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
24. Mutations in TBC1D24, a gene associated with epilepsy, also cause nonsyndromic deafness DFNB86.
- Author
-
Rehman AU, Santos-Cortez RL, Morell RJ, Drummond MC, Ito T, Lee K, Khan AA, Basra MA, Wasif N, Ayub M, Ali RA, Raza SI, Nickerson DA, Shendure J, Bamshad M, Riazuddin S, Billington N, Khan SN, Friedman PL, Griffith AJ, Ahmad W, Riazuddin S, Leal SM, and Friedman TB
- Subjects
- Alleles, Amino Acid Sequence, Chromosomes, Human, Pair 16 genetics, Consanguinity, Deafness genetics, Exome, Exons, Female, GTPase-Activating Proteins, Genes, Recessive, Genetic Loci, Genome-Wide Association Study, Heterozygote, Homozygote, Humans, Male, Membrane Proteins, Molecular Sequence Data, Nerve Tissue Proteins, Pakistan, Pedigree, Phenotype, Polymorphism, Single Nucleotide, RNA, Messenger genetics, RNA, Messenger metabolism, Sequence Analysis, DNA, Carrier Proteins genetics, Epilepsy genetics, Mutation
- Abstract
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., (Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
25. Perrault syndrome is caused by recessive mutations in CLPP, encoding a mitochondrial ATP-dependent chambered protease.
- Author
-
Jenkinson EM, Rehman AU, Walsh T, Clayton-Smith J, Lee K, Morell RJ, Drummond MC, Khan SN, Naeem MA, Rauf B, Billington N, Schultz JM, Urquhart JE, Lee MK, Berry A, Hanley NA, Mehta S, Cilliers D, Clayton PE, Kingston H, Smith MJ, Warner TT, Black GC, Trump D, Davis JR, Ahmad W, Leal SM, Riazuddin S, King MC, Friedman TB, and Newman WG
- Subjects
- ATP-Dependent Proteases metabolism, Adenosine Triphosphate metabolism, Adolescent, Adult, Female, Homozygote, Humans, In Situ Hybridization, Male, Mitochondria genetics, Pedigree, Phenotype, Young Adult, ATP-Dependent Proteases genetics, Endopeptidase Clp genetics, Exome genetics, Genes, Recessive, Gonadal Dysgenesis, 46,XX etiology, Hearing Loss, Sensorineural etiology, Mitochondria enzymology, Mutation genetics
- Abstract
Perrault syndrome is a genetically and clinically heterogeneous autosomal-recessive condition characterized by sensorineural hearing loss and ovarian failure. By a combination of linkage analysis, homozygosity mapping, and exome sequencing in three families, we identified mutations in CLPP as the likely cause of this phenotype. In each family, affected individuals were homozygous for a different pathogenic CLPP allele: c.433A>C (p.Thr145Pro), c.440G>C (p.Cys147Ser), or an experimentally demonstrated splice-donor-site mutation, c.270+4A>G. CLPP, a component of a mitochondrial ATP-dependent proteolytic complex, is a highly conserved endopeptidase encoded by CLPP and forms an element of the evolutionarily ancient mitochondrial unfolded-protein response (UPR(mt)) stress signaling pathway. Crystal-structure modeling suggests that both substitutions would alter the structure of the CLPP barrel chamber that captures unfolded proteins and exposes them to proteolysis. Together with the previous identification of mutations in HARS2, encoding mitochondrial histidyl-tRNA synthetase, mutations in CLPP expose dysfunction of mitochondrial protein homeostasis as a cause of Perrault syndrome., (Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
26. Loss-of-function mutations of ILDR1 cause autosomal-recessive hearing impairment DFNB42.
- Author
-
Borck G, Ur Rehman A, Lee K, Pogoda HM, Kakar N, von Ameln S, Grillet N, Hildebrand MS, Ahmed ZM, Nürnberg G, Ansar M, Basit S, Javed Q, Morell RJ, Nasreen N, Shearer AE, Ahmad A, Kahrizi K, Shaikh RS, Ali RA, Khan SN, Goebel I, Meyer NC, Kimberling WJ, Webster JA, Stephan DA, Schiller MR, Bahlo M, Najmabadi H, Gillespie PG, Nürnberg P, Wollnik B, Riazuddin S, Smith RJ, Ahmad W, Müller U, Hammerschmidt M, Friedman TB, Riazuddin S, Leal SM, Ahmad J, and Kubisch C
- Subjects
- Animals, Chromosome Mapping, Chromosomes, Human, Pair 3 genetics, Consanguinity, Ear, Inner, Female, Genetic Linkage, Genotype, Humans, In Situ Hybridization, Lod Score, Male, Mice, Pedigree, Zebrafish, Codon, Nonsense genetics, Genes, Recessive genetics, Genetic Predisposition to Disease, Hearing Loss genetics, Receptors, Cell Surface genetics
- Abstract
By using homozygosity mapping in a consanguineous Pakistani family, we detected linkage of nonsyndromic hearing loss to a 7.6 Mb region on chromosome 3q13.31-q21.1 within the previously reported DFNB42 locus. Subsequent candidate gene sequencing identified a homozygous nonsense mutation (c.1135G>T [p.Glu379X]) in ILDR1 as the cause of hearing impairment. By analyzing additional consanguineous families with homozygosity at this locus, we detected ILDR1 mutations in the affected individuals of 10 more families from Pakistan and Iran. The identified ILDR1 variants include missense, nonsense, frameshift, and splice-site mutations as well as a start codon mutation in the family that originally defined the DFNB42 locus. ILDR1 encodes the evolutionarily conserved immunoglobulin-like domain containing receptor 1, a putative transmembrane receptor of unknown function. In situ hybridization detected expression of Ildr1, the murine ortholog, early in development in the vestibule and in hair cells and supporting cells of the cochlea. Expression in hair cell- and supporting cell-containing neurosensory organs is conserved in the zebrafish, in which the ildr1 ortholog is prominently expressed in the developing ear and neuromasts of the lateral line. These data identify loss-of-function mutations of ILDR1, a gene with a conserved expression pattern pointing to a conserved function in hearing in vertebrates, as underlying nonsyndromic prelingual sensorineural hearing impairment., (Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
27. Noncoding mutations of HGF are associated with nonsyndromic hearing loss, DFNB39.
- Author
-
Schultz JM, Khan SN, Ahmed ZM, Riazuddin S, Waryah AM, Chhatre D, Starost MF, Ploplis B, Buckley S, Velásquez D, Kabra M, Lee K, Hassan MJ, Ali G, Ansar M, Ghosh M, Wilcox ER, Ahmad W, Merlino G, Leal SM, Riazuddin S, Friedman TB, and Morell RJ
- Subjects
- 3' Untranslated Regions genetics, Alternative Splicing, Animals, Cochlea pathology, Consanguinity, DNA Mutational Analysis, Exons, Female, Hearing Loss pathology, India, Introns, Male, Mice, Mice, Knockout, Molecular Sequence Data, Mutation, Pakistan, Pedigree, Hearing Loss genetics, Hepatocyte Growth Factor genetics
- Abstract
A gene causing autosomal-recessive, nonsyndromic hearing loss, DFNB39, was previously mapped to an 18 Mb interval on chromosome 7q11.22-q21.12. We mapped an additional 40 consanguineous families segregating nonsyndromic hearing loss to the DFNB39 locus and refined the obligate interval to 1.2 Mb. The coding regions of all genes in this interval were sequenced, and no missense, nonsense, or frameshift mutations were found. We sequenced the noncoding sequences of genes, as well as noncoding genes, and found three mutations clustered in intron 4 and exon 5 in the hepatocyte growth factor gene (HGF). Two intron 4 deletions occur in a highly conserved sequence that is part of the 3' untranslated region of a previously undescribed short isoform of HGF. The third mutation is a silent substitution, and we demonstrate that it affects splicing in vitro. HGF is involved in a wide variety of signaling pathways in many different tissues, yet these putative regulatory mutations cause a surprisingly specific phenotype, which is nonsydromic hearing loss. Two mouse models of Hgf dysregulation, one in which an Hgf transgene is ubiquitously overexpressed and the other a conditional knockout that deletes Hgf from a limited number of tissues, including the cochlea, result in deafness. Overexpression of HGF is associated with progressive degeneration of outer hair cells in the cochlea, whereas cochlear deletion of Hgf is associated with more general dysplasia.
- Published
- 2009
- Full Text
- View/download PDF
28. Null mutations in LTBP2 cause primary congenital glaucoma.
- Author
-
Ali M, McKibbin M, Booth A, Parry DA, Jain P, Riazuddin SA, Hejtmancik JF, Khan SN, Firasat S, Shires M, Gilmour DF, Towns K, Murphy AL, Azmanov D, Tournev I, Cherninkova S, Jafri H, Raashid Y, Toomes C, Craig J, Mackey DA, Kalaydjieva L, Riazuddin S, and Inglehearn CF
- Subjects
- Chromosome Mapping, Consanguinity, Glaucoma congenital, Humans, Latent TGF-beta Binding Proteins metabolism, Mutation, Pedigree, Ciliary Body metabolism, Glaucoma genetics, Latent TGF-beta Binding Proteins genetics
- Abstract
Primary congenital glaucoma (PCG) is an autosomal-recessive condition characterized by high intraocular pressure (IOP), usually within the first year of life, which potentially could lead to optic nerve damage, globe enlargement, and permanent loss of vision. To date, PCG has been linked to three loci: 2p21 (GLC3A), for which the responsible gene is CYP1B1, and 1p36 (GLC3B) and 14q24 (GLC3C), for which the genes remain to be identified. Here we report that null mutations in LTBP2 cause PCG in four consanguineous families from Pakistan and in patients of Gypsy ethnicity. LTBP2 maps to chromosome 14q24.3 but is around 1.3 Mb proximal to the documented GLC3C locus. Therefore, it remains to be determined whether LTBP2 is the GLC3C gene or whether a second adjacent gene is also implicated in PCG. LTBP2 is the largest member of the latent transforming growth factor (TGF)-beta binding protein family, which are extracellular matrix proteins with multidomain structure. It has homology to fibrillins and may have roles in cell adhesion and as a structural component of microfibrils. We confirmed localization of LTBP2 in the anterior segment of the eye, at the ciliary body, and particularly the ciliary process. These findings reveal that LTBP2 is essential for normal development of the anterior chamber of the eye, where it may have a structural role in maintaining ciliary muscle tone.
- Published
- 2009
- Full Text
- View/download PDF
29. Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35.
- Author
-
Collin RW, Kalay E, Tariq M, Peters T, van der Zwaag B, Venselaar H, Oostrik J, Lee K, Ahmed ZM, Caylan R, Li Y, Spierenburg HA, Eyupoglu E, Heister A, Riazuddin S, Bahat E, Ansar M, Arslan S, Wollnik B, Brunner HG, Cremers CW, Karaguzel A, Ahmad W, Cremers FP, Vriend G, Friedman TB, Riazuddin S, Leal SM, and Kremer H
- Subjects
- Amino Acid Sequence, Chromosomes, Human, Pair 14, DNA Mutational Analysis, Ear, Inner embryology, Ear, Inner metabolism, Female, Gene Duplication, Genes, Recessive, Genetic Linkage, Humans, Male, Microsatellite Repeats, Models, Molecular, Molecular Sequence Data, Mutation, Missense, Pedigree, Protein Isoforms chemistry, Protein Isoforms genetics, Receptors, Cytoplasmic and Nuclear chemistry, Receptors, Estrogen chemistry, Sequence Alignment, Hearing Loss genetics, Receptors, Cytoplasmic and Nuclear genetics, Receptors, Estrogen genetics
- Abstract
In a large consanguineous family of Turkish origin, genome-wide homozygosity mapping revealed a locus for recessive nonsyndromic hearing impairment on chromosome 14q24.3-q34.12. Fine mapping with microsatellite markers defined the critical linkage interval to a 18.7 cM region flanked by markers D14S53 and D14S1015. This region partially overlapped with the DFNB35 locus. Mutation analysis of ESRRB, a candidate gene in the overlapping region, revealed a homozygous 7 bp duplication in exon 8 in all affected individuals. This duplication results in a frame shift and premature stop codon. Sequence analysis of the ESRRB gene in the affected individuals of the original DFNB35 family and in three other DFNB35-linked consanguineous families from Pakistan revealed four missense mutations. ESRRB encodes the estrogen-related receptor beta protein, and one of the substitutions (p.A110V) is located in the DNA-binding domain of ESRRB, whereas the other three are substitutions (p.L320P, p.V342L, and p.L347P) located within the ligand-binding domain. Molecular modeling of this nuclear receptor showed that the missense mutations are likely to affect the structure and stability of these domains. RNA in situ hybridization in mice revealed that Esrrb is expressed during inner-ear development, whereas immunohistochemical analysis showed that ESRRB is present postnatally in the cochlea. Our data indicate that ESRRB is essential for inner-ear development and function. To our knowledge, this is the first report of pathogenic mutations of an estrogen-related receptor gene.
- Published
- 2008
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.