Dr. Ahmed received his Bachelor and PhD degrees from the University of Punjab, Pakistan. He accomplished his pre-doctoral as well as his post-doctoral trainings at the National Institute for Deafness and Communication Disorders, NIDCD/NIH. In 2009 he joined the Cincinnati Children’s Hospital Medical Center, and University of Cincinnati, Cincinnati, Ohio as an Assistant Professor of Ophthalmology, Otolaryngology and Human Genetics. He was subsequently promoted to Associate Professor with tenure in 2013. In July 2014, Dr. Ahmed joined the University of Maryland as an Associate Professor of Otorhinolaryngology, Ophthalmology and Biochemistry.
Dr Ahmed’s scientific accomplishments have earned several national and international awards, including Career Development Award by the RPB Foundation and a Medal of Honor by the President of Pakistan. He has been continuously funded as a principal investigator since 2007.
Dr. Ahmed long-term goal is to understand how the retinal and inner ear sensory epithelia develop and function. His lab study inherited human disorders of retina and inner ear, like Usher syndrome (USH) and Oculocutaneous Albinism (OCA) to improve our understanding of these organs at the molecular level, to study the pathophysiology of these disorders in animal models for the purpose of developing new strategies to prevent and treat these neurosensory disorders. The studies under investigation are designed to answer the following broad questions: What are the precise mechanisms of various forms of hearing and vision dysfunction? What are the genetic factors that determine light sensitivity? How do the pathogenic mutations in disease-causing genes affect the ear, eye and skin structure and function? And which molecules or genetic factors can exacerbate and/or mitigate the effects of disease-causing genes? For these studies, families segregating inherited USH and OCA are being collected. Mutant mouse and zebrafish models have been developed and his lab evaluates them to understand the function of new proteins. Functional analysis of the newly identified genes associated with deaf-blindness and OCA promises new insights into the molecular mechanisms of vision and auditory development and functions and will facilitate the rational design of potential therapies.
Here are a few examples of ongoing projects in Dr. Ahmed’s lab:
Role of Calcium and Integrin binding protein CIB2 in the inner ear and retina
In our recent study, we have identified 57 consanguineous Pakistani families segregating non-syndromic hearing impairment (DFNB48) or Usher syndrome type I (USH1J) linked to the mutations in CIB2, a gene that encodes a calcium binding protein. We have identified at least 3 different mutations in CIB2 that lead to non-syndromic hearing loss and one mutation causing Usher syndrome (Fig. 1). To date, these mutations are the most common and prevalent genetic cause of non-syndromic hearing loss in Pakistan. But mutations in CIB2 are not confined to Pakistani population. We have recently identified additional mutations in CIB2 that cause hearing loss in Turkish, Danish and US population. Identification of this new gene means improvement in our genetic diagnostic abilities, genetic counseling and molecular epidemiology of hearing loss.
The reason why we think this particular Usher syndrome might be better suited for future interventions is because of the nature of the protein discovered. All previous mutations associated with Usher syndrome affect the proteins involved in building the structure of the sensory cells. This means that the sensory cells are likely to be malformed or disorganized in an adult organism. Of course, correcting the structural pathology is a very challenging task. In contrast, the mutations of CIB2 that we discovered seem to have much more subtle effects. We speculate that these mutations may affect only the calcium homeostasis in the sensory cells, although more functional studies are needed to test this hypothesis and function of CIB2 in the inner ear and retina. To this end, we have developed several CIB2 mouse lines. We are currently working to characterize the hearing and the visual phenotype of these mice through calcium and electronic microcopy imaging, immunological and physiological studies.
- Fig. 1
Genetics of Oculocutaneous Albinism: predisposition for Skin Cancer
Our lab is currently studying Oculocutaneous albinism (OCA), which is a form of albinism that involves the eye, skin, and often hair. This recessive disorder is caused by defects in the melanin synthesis pathway. Polymorphisms in some of the pigmentary pathway genes (e.g. TYR, OCA2, TYRP1 and SLC45A2) increase susceptibility for skin cancer, which affects all ages, genders and societies worldwide. Malignant melanoma is the major cause of deaths from skin cancer and a large number of studies revealed that the risk of malignant melanoma correlated with genetic, personal characteristics and a person’s ultraviolet (UV) exposure behavior. We are ascertaining large families (Fig. 2) segregating OCA phenotype from various populations around the globe. There are many cases of OCA in which the causative gene remains unknown. Therefore, a need clearly exists for further genetic understanding of this disease, as does the opportunity to minimize the cases of preventable skin cancers. We are currently working to identify novel genes involved in these disorders.
- Fig. 2
- Arnaud P. Giese, PhD, Post-doctoral Associate
- Mohsin Shahzad, PhD, Post-doctoral Associate
- Fareeha Zulfiqar, PhD, Post-doctoral Associate
- Thomas Jaworek, BS, Research Technician
Grants & Contracts:
National Institute of Deafness and Other Communication Disorders/National Institutes of Health, Research Project Grant- R01DC012564. “Usher proteins in the inner ear structure and function”. Role: PI
National Institute of Deafness and Other Communication Disorders/National Institutes of Health, Research Project Grant-R01 (1R01 DC011803-01A1). “Identifying Genes for Non-syndromic Recessive Deafness- A Collaborative Study”. Role: Co-Investigator
- Shaikh RS, Reuter P, Sisk RA, Kausar T, Shahzad M, Maqsood MI, Yousif A, Ali M, Riazuddin S, Wissinger B, Ahmed ZM. Homozygous missense variant in the human CNGA3 channel causes cone-rod dystrophy. Eur J Hum Genet 2014 Available online.
- Santos-Cortez RLP, Lee K, Giese AP, Ansar M, Amin-ud-din M, Rehn K, Wang F, Chiu I, Smith JD, University of Washington Center for Mendelian Genomics, Nickerson DA, Ahmed ZM, Ahmad W, Riazuddin S, Leal SM. Adenylate Cyclase 1 (ADCY1) mutations cause recessive low-frequency hearing impairment in humans and defects in hair cell function and hearing in zebrafish. Hum Mol Genet. 2014: 23(12):3289-3298.
- Cideciyan AV, Hufnagel RB, Carroll J, Sumaroka A, Luo X, Schwartz SB, Dubra A, Land M, Michaelides M, Gardner JC, Hardcastle AJ, Moore AT, Sisk RA, Ahmed ZM, Kohl S, Wissinger B, Jacobson SG. Human cone visual pigment deletions spare sufficient photoreceptors to warrant gene therapy. Hum Gene Ther. 2013: 24:1-14.
- Indzhykulian AA, Stepanyan R, Nelina A, Spinelli KJ, Ahmed ZM, Belyantseva IA, Friedman TB, Barr-Gillespie PG, Frolenkov GI. Molecular remodeling of tip links underlies mechanosensory regeneration in auditory hair cells. PLoS Biol. 2013: 11(6):e1001583.
- Kausar T, Jaworek TJ, Bhatti MA, Sadia S, Ali M, Shaikh RS, Ahmed ZM. Genetic studies of TYRP1 and SLC45A2 in Pakistani patients with nonsyndromic oculocutaneous albinism. J Invest Dermatol. 2013: 133(4):1099-1102.
- Kausar T, Tariq N, Ali M, Shaikh RS, Ahmed ZM.OCA5, a novel locus for non-syndromic oculocutaneous albinism, maps to chromosome 4q24. Clin Genet. 2013: 84(1):91-3.
- Riazuddin S, Belyantseva I, Giese A, Lee K, Indzhykulian AA, Nandamuri SP, Yousaf R, Sinha GP, Lee S, Terrell D, Hegde RS, Ali RA, Anwar S, Andrade-Elizondo PB, Sirmaci A, Parise LV, Basit S, Wali A, Ayub M, Ansar M, Ahmad W, Khan SN, Akram J, Tekin M, Riazuddin S, Cook T, Buschbeck EK, Frolenkov GI, Leal SM, Friedman TB, Ahmed ZM. Alterations of the CIB2 calcium and integrin binding protein cause Usher syndrome type 1J and nonsyndromic deafness DFNB48. Nat Genet 2012: 44(11):1265-1271.
- Jaworek TJ, Kausar T, Bell SM, Tariq N, Maqsood MI, Sohail A, Ali M, Iqbal F, Rasool S, Riazuddin S, Shaikh RS, Ahmed ZM*. Molecular genetic studies and delineation of the Oculocutaneous Albinism phenotype in the Pakistani population. Orphanet J Rare Dis June 26 2012; 7:44.
- Ahmed ZM, Yousaf R, Lee BC, Khan SN, Lee S, Lee K, Husnain T, Rehman AU, Bonneux, S, Ansar M, Ahmad W, Leal SM, Gladyshev VN, Belyantseva IA, Van Camp G, Riazuddin S, Friedman TB, Riazuddin S. Functional null mutations of MSRB3 encoding methionine sulfoxide reductase are associated with human deafness DFNB74. Am J Hum Genet 2011: 88(1):19-29.
- Riazuddin SA, Shahzadi A, Zeitz C, Ahmed ZM, Ayyagari R, Chavali VR, Ponferrada VG, Audo I, Michiels C, Lancelot ME, Nasir IA, Zafar AU, Khan SN, Husnain T, Jiao X, MacDonald IM, Riazuddin S, Sieving PA, Katsanis N, Hejtmancik JF. A mutation in SLC24A1 implicated in autosomal-recessive congenital stationary night blindness. Am J Hum Genet 2010: 87(4):523-531.
- Kitajiri SI, Sakamoto T, Belyantseva IA, Goodyear RJ, Stepanyan R, Fujiwara I, Bird JE, Riazuddin S, Riazuddin S, Ahmed ZM, Hinshaw JE, Sellers J, Bartles JR, Hammer JA, Richardson GP, Griffith AJ, Frolenkov GI, Friedman TB. Actin-bundling protein TRIOBP forms resilient rootlets of hair cell stereocilia essential for hearing. Cell 2010: 141:786-798.
- Schultz JM, Khan SK, Ahmed ZM, Riazuddin S, Waryah AA, Chhatre D, Starost MF, Ploplis B, Buckley S, Velasquez 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, Morell RJ. Noncoding mutations of HGF3 are associated with nonsyndromic recessive deafness, DFNB39. Am J Hum Genet 2009: 85(1):25-39.
- Ahmed ZM, Masmoudi S, Kalay E, Belyantseva IA, Mosrati MA, Collin RWJ, Riazuddin S, Hmani-Aifa M, Venselaar H, Kawar MN, Abdelaziz T, Zwaag BVD, Khan SY, Ayadi L, Riazuddin SA, Morell RJ, Griffith AJ, Charfedine I, Çaylan R, Oostrik J, Karaguzel A, Ghorbel A, Riazuddin S, Friedman TB, Ayadi H, Kremer H. Mutations of LRTOMT, a fusion gene with alternative reading frames, cause nonsyndromic deafness in humans. Nat Genet 2008: 40(11):1335-1340.
- Riazuddin S, Ahmed ZM, Fanning AS, Lagziel A, Kitajiri S, Ramzan K, Khan SN, Chattaraj P, Friedman PL, Anderson JM, Belyantseva IA, Forge A, Riazuddin S, Friedman TB. Tricellulin is a tight-junction protein necessary for hearing. Am J Hum Genet 2006: 79(6):1040-1051.
- Ahmed ZM, Goodyear R, Riazuddin S, Lagziel A, Behra M, Burgess SM, Wilcox ER, Riazuddin S, Griffith AJ, Frolenkov G, Belyantseva IA, Richardson G, Friedman TB. The tip link antigen, a protein associated with the transduction complex of sensory hair cells, is protocadherin-15. J Neuroscience 2006: 26:7022-7034.
- Haywood-Watson II RJL, Ahmed ZM, Kjellstrom S, Bush RA, Takada Y, Alagramam KN, Hampton LL,Battey JF, Sieving PA, Friedman TB. Ames waltzer deaf mice have reduced electroretinogram amplitudes and complex alternative splicing of Pcdh15 transcripts. IOVS 2006: 47(7):3074-3084.
- Riazuddin S, Khan SN, Ahmed ZM, Ghosh M, Caution K, Nazli S, Kabra M, Zafar AU, Chen K, Naz S, Paven W, Antonellis A, Pavan WJ, Green ED, Wilcox ER, Friedman PL, Morell RJ, Riazuddin S, Friedman TB. Mutations in TRIOBP, encoding a putative cytoskeletal organizing protein, are associated with nonsyndromic recessive deafness. Am J Hum Genet2006:78(1):137-143.
- Belyantseva IA, Boger ET, Naz S, Frolenkov GI, Sellers JR, Ahmed ZM, Griffith AJ, Friedman TB. Myosin-XVa is required for tip localization of whirlin and differential elongation of hair-cell stereocilia. Nat Cell Bio 2005: 7(2):148-156.
- Ahmed ZM, Riazuddin S, Ahmad J, Bernstein SL, Guo Y, Sabir MF, Sieving P, Riazuddin S, Griffith AJ, Friedman TB, Belyantseva IA, Wilcox ER. PCDH15 is expressed in the neurosensory epithelium of the eye and ear and mutant alleles are responsible for both USH1F and DFNB23. Hum Mol Genet 2003: 12 (24):3215-3223.
- Ben-Yosef T, Ness SL, Madeo AC, Bar-Lev A, Wolfman JH, Ahmed ZM, Desnick RJ, Avraham KB, Ostrer H, Oddoux C, Griffith AJ, Friedman TB. A mutation of PCDH15 among Ashkenazi Jews with type I Usher syndrome. N Engl J Med 2003: 348(17):1664-1670.
- Ahmed ZM, Morell RJ, Riazuddin S, Gropman A, Shaukat S, Ahmad MM, Mohiddin SA, Fananapazir L, Caruso RC, Husnain T, Khan SN, Riazuddin S, Griffith AJ, Friedman TB, Wilcox ER. Mutations of MYO6 are associated with recessive deafness DFNB37. Am J Hum Genet 2003: 72:1315–1322.
- Kurima K, Peters LM, Yang Y, Riazuddin S, Ahmed ZM, Naz S, Arnaud D, Drury S, Mo J, Makishima T, Ghosh M, Menon PSN, Deshmukh D, Oddoux C, Ostrer H, Khan S, Riazuddin S, Deininger PL, Hampton LL, Sullivan SL, Battey JFJr., Keats BJB, Wilcox ER, Friedman TB, Griffith AJ. Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function. Nat Genet 2002: 30(3):277-284.
- Ahmed ZM, Riazuddin S, Bernstein SL, Ahmed Z, Khan S, Griffith AJ, Morell RJ, Friedman TB, Riazuddin S, Wilcox ER. Mutations of the protocadherin gene PCDH15 cause Usher syndrome type 1F. Am J Hum Genet 2001: 69(1):25-34.
- Bork JM, Peters LM, Riazuddin S, Bernstein SL, Ahmed ZM, Ness SL, Polomeno R, Ramesh A, Schloss M, Srisailpathy CR, Wayne S, Bellman S, Desmukh D, Ahmed Z, Khan SN, Kaloustian VM, Li XC, Lalwani A, Riazuddin S, Bitner-Glindzicz M, Nance WE, Liu XZ, Wistow G, Smith RJ, Griffith AJ, Wilcox ER, Friedman TB, Morell RJ. Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23. Am J Hum Genet 2001: 68(1):26-37.
- Riazuddin S, Castelein CM, Ahmed ZM, Lalwani AK, Mastroianni MA, Naz S, Smith TN, Liburd NA, Friedman TB, Griffith AJ, Riazuddin S, Wilcox ER. Dominant modifier DFNM1 suppresses recessive deafness DFNB26. Nat Genet 2000: 26(4):431-434.
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