Andrew J. Griffith, M.D., Ph.D.
Molecular Biology and Genetics Section
Porter Neuroscience Research Center
35A Convent Drive, Room GF103
Bethesda, MD 20892-3729 For U.S. Postal Service
Bethesda, MD 20814 For other carriers (FedEx, UPS, etc.)
Phone: (301) 402-2829
Dr. Griffith received M.D. and Ph.D. degrees from Yale University. He completed an Otolaryngology-Head and Neck Surgery residency at the University of Michigan, where he also received fellowship training in the laboratory of Dr. Miriam Meisler in the Department of Human Genetics.
On this page:
Dr. Griffith examines a CT scan
Basic molecular biology and genetic research is carried out in the Molecular Biology and Genetics Section. Audiology Unit research activities include audiological and vestibular assessment of human subjects participating in clinical research protocols of the Otolaryngology Branch, the NIDCD, or other NIH Institutes and Centers.
Ms. Julie Muskett is the Genetic Counselor for the NIDCD. Her responsibilities include coordinating clinical research protocols in the Otolaryngology Branch and the Laboratory of Molecular Genetics, and genetic counseling of subjects participating in NIDCD research studies.
Subjects Needed for Research Studies
The Otolaryngology Branch is seeking research subjects from families to participate in research studies in the following areas:
Information for Patients
Information on hearing loss associated with enlargement of the vestibular aqueduct, Pendred syndrome, and the PDS/SLC26A4 gene can be found on our EVA information pages.
Axial T2-weighted fast spin echo MRI images of the right temporal bone showing enlargement of the endolymphatic system (known as EVA) when visualized on CT scans.
Julie Muskett, Genetic Counselor (Send e-mail)
Molecular Biology and Genetics Section
Schematic illustration of the mammalian auditory system (from Griffith and Friedman, Nature Genetics, 1999). View larger image.
Our laboratory identifies and characterizes genes, molecules, and mechanisms underlying hearing and hereditary hearing loss. We use molecular biologic and genetic approaches, human and mouse models, as well as heterologous cell culture expression systems. A variety of techniques—including in situ hybridization, immunohistochemistry, RT-PCR, Western and Northern blotting, and immunoprecipitation—are used to analyze gene and protein expression, function, and interactions.
Current Areas of Interest
We identified a novel gene, TMC1, which underlies dominant DFNA36 and recessive DFNB7/B11 deafness in humans. Dominant and recessive mutations in the mouse Tmc1 gene underlie deafness in the Beethoven (Bth) and deafness (dn) mouse mutants, respectively, which exhibit rapid degeneration of the neurosensory hair cells of the cochleae. TMC1 protein has no sequence similarities to proteins or domains of known function, but has six transmembrane domains whose topologic organization suggests a role as an ion channel or transporter. There are seven other members of the mammalian TMC gene family, and we are using mutant mouse models to identify the function(s) of Tmc1 and these other Tmc genes. TMC1 and TMC2 are functionally redundant proteins that are required for mechanotransduction at the tips of stereocilia of mouse inner ear hair cells. TMC1 and TMC2 may thus be components of the mechanotransduction channel, or required for its structure, function or development. We are using a variety of approaches to distinguish among these possibilities.
Schematic illustration of TMC1 showing predicted transmembrane topology and human and mouse mutations causing deafness. View larger image.
A second project is the molecular genetic analysis of human hearing loss associated with enlargement of the vestibular aqueduct (EVA). EVA is the most commonly observed inner ear malformation in children with hearing loss. In many cases EVA is associated with mutations in the Pendred syndrome gene PDS/SLC26A4, which encodes an integral membrane protein that is thought to transport or exchange chloride, iodide, bicarbonate, or other bases in the inner ear. Our current projects include the identification of novel genes for EVA in human patients, and the generation and characterization of novel mouse models for EVA. We are using these models to better understand the pathophysiology of hearing loss in EVA and, in the future, explore potential therapeutic agents to prevent, reduce, or reverse hearing loss in EVA.
Parna Chattaraj, M.S., Biologist (Send e-mail)
Keiji Honda, Ph.D., Postdoc Visiting Fellow (Send e-mail)
Kiyoto Kurima, Ph.D., Staff Scientist (Send e-mail)
Julie Muskett, Genetic Counselor (Send e-mail)
Hiroshi Nakanishi, M.D., Ph.D., Visiting Fellow (Send e-mail)
Ayako Nishio, M.D., Visiting Fellow (Send e-mail)
Click for larger image
- Rehman AU, Santos-Cortez RLP, Morell RJ, Drummond MC, Ito T, Lee K, Khan AA, Basra MAR, 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, Friedman TB. 2014. Mutations in TBC1D24, a gene associated with epilepsy, also cause nonsyndromic deafness DFNB86. Am. J. Hum. Genet. 94:144-152.
- Ito T, Li X, Kurima K, Choi BY, Wangemann P, Griffith AJ. 2014. Slc26a4-insufficiency causes fluctuating sensorineural hearing loss and stria vascularis dysfunction. Neurobiol. Dis. 66:53-65.
- Ito T, Muskett K, Chattaraj P, Choi BY, Lee KY, Zalewski CK, King KA, Li X, Wangemann P, Shawker T, Brewer CC, Alper SL, Griffith AJ. 2013. SLC26A4 mutation testing for hearing loss associated with enlargement of the vestibular aqueduct. World J. Otorhinolaryngol. 3:26-34.
- Totonchy MB, Tamura D, Pantell MS, Zalewski C, Bradford PT, Merchant SN, Nadol J, Khan SG, Schiffman R, Pierson TM, Wiggs E, Griffith AJ, DiGiovanna JJ, Kraemer KH, Brewer CC. 2013. Auditory analysis of xeroderma pigmentosum 1971-2012: hearing function, sun sensitivity and DNA repair predict neurological degeneration. Brain. 136:194-208.
- Li X, Sanneman JD, Harbridge DG, Zhou F, Ito T, Nelson R, Chambrey R, Eladari D, Miesner T, Griffith AJ, Marcus DC and Wangemann P. 2013. SLC26A4 targeted to the endolymphatic sac rescues hearing and balance in Slc26a4 mutant mice. PLoS Genet. 9:e1003641.
- Pan B, Géléoc GS, Asai Y, Horwitz GC, Kurima K, Ishikawa K, Kawashima Y, Griffith AJ, Holt JR. 2013. TMC1 and TMC2 are components of the mechanotransduction channel in hair cells of the mammalian inner ear. Neuron. 79:504-515.
- Tan X, Anzick S, Khan SG, Ueda T, Stone G, DiGiovanna JJ, Tamura D, Wattendorf D, Busch D, Brewer C, Zalewski C, Butman JA, Griffith AJ, Meltzer P, Kraemer KH. 2013. Chimeric negative regulation of p14ARF and TBX1 induced by a 9p21;22q11.2 translocation associated with melanoma, deafness and DNA repair deficiency. Hum. Mutat. 34:1250-1259.
- Chattaraj P, Reimold FR, Muskett JA, Shmukler BE, Chien WW, Madeo AC, Pryor SP, King KA, Zalewski CK, Butman JA, Brewer CC, Kenna MA, Alper SL, Griffith AJ. 2013. Use of SLC26A4 mutation testing for unilateral enlargement of the vestibular aqueduct. JAMA Otolaryngol. Head Neck Surg. 139:907-913.
- Shepard K, Ito T, Griffith AJ. 2012. Extracting energy from the inner ear. Nat. Biotechnol. 30:1204-1205.
- Ito T, Choi BY, King KA, Zalewski CK, Muskett J, Chattaraj P, Shawker T, Reynolds JC, Butman JA, Brewer CC, Wangemann P, Alper SL, Griffith AJ. SLC26A4 Genotypes and Phenotypes Associated with Enlargement of the Vestibular Aqueduct. Cell Physiol Biochem. 2011;28(3):545-52.
- Kawashima Y, Géléoc GS, Kurima K, Labay V, Lelli A, Asai Y, Makishima T,Wu DK, Della Santina CC, Holt JR, Griffith AJ. Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes. J Clin Invest. 2011 Dec 1;121(12):4796-809. doi: 10.1172/JCI60405. Epub 2011 Nov 21.
- Hertzano R, Elkon R, Kurima K, Morrisson A, Chan SL, Sallin M, Biedlingmaier A, Darling DS, Griffith AJ, Eisenman DJ, Strome SE. Cell type-specific transcriptome analysis reveals a major role for Zeb1 and miR-200b in mouse inner ear morphogenesis. PLoS Genet. 2011 Sep;7(9):e1002309. Epub 2011 Sep 29.
- Kurima K, Hertzano R, Gavrilova O, Monahan K, Shpargel KB, Nadaraja G, Kawashima Y, Lee KY, Ito T, Higashi Y, Eisenman DJ, Strome SE, Griffith AJ. A noncoding point mutation of Zeb1 causes multiple developmental malformations and obesity in Twirler mic. PLoS Genet. 2011 Sep;7(9):e1002307. Epub 2011 Sep 29.
- Choi BY, Kim HM, Ito T, Lee KY, Li X, Monahan K, Wen Y, Wilson E, Kurima K, Saunders TL, Petralia RS, Wangemann P, Friedman TB, Griffith AJ. Mouse model of enlarged vestibular aqueducts defines temporal requirement of Slc26a4 expression for hearing acquisition. J Clin Invest. 2011 Nov 1;121(11):4516-25. doi: 10.1172/JCI59353.
- Schultz JM, Bhatti R, Madeo AC, Turriff A, Muskett JA, Zalewski CK, King KA, Ahmed ZM, Riazuddin S, Ahmad N, Hussain Z, Qasim M, Kahn SN, Meltzer MR, Liu XZ, Munisamy M, Ghosh M, Rehm HL, Tsilou ET, Griffith AJ, Zein WM, Brewer CC, Riazuddin S, Friedman TB. Allelic hierarchy of CDH23 mutations causing non-syndromic deafness DFNB12 or Usher syndrome USH1D in compound heterozygote. J Med Genet. 2011 Nov;48(11):767-75.
- Griffith AJ, Wangemann P. Hearing loss associated with enlargement of the vestibular aqueduct: Mechanistic insights from clinical phenotypes, genotypes, and mouse models. Hear Res. 2011 Nov;281(1-2):11-7.
- Iwata T, Yoshida T, Teranishi M, Murata Y, Hayashi Y, Kanou Y, Griffith AJ, Nakashima T. Influence of dietary iodine deficiency on the thyroid gland in Slc26a4-null mutant mice. Thyroid Res. 2011 Jun 20;4(1):10. [Epub ahead of print]
- Choi BY, Muskett J, King KA, Zalewski CK, Shawker T, Reynolds JC, Butman JA, Brewer CC, Stewart AK, Alper SL, Griffith AJ. Hereditary hearing loss with thyroid abnormalities. Adv Otorhinolaryngol. 2011;70:43-9. Epub 2011 Feb 24. Review.
- Riazuddin S, Ahmed ZM, Hegde RS, Khan SN, Nasir I, Shaukat U, Riazuddin S, Butman JA, Griffith AJ, Friedman TB, Choi BY. Variable expressivity of FGF3 mutations associated with deafness and LAMM syndrome. BMC Med Genet. 2011 Feb 9;12:21.
- Labay V, Weichert RM, Makishima T, Griffith AJ. Topology of transmembrane channel-like gene 1 protein. Biochemistry. 2010 Oct 5;49(39):8592-8. Epub 2010 Sep 8.
- Kitajiri S, 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 3rd, Richardson GP, Griffith AJ, Frolenkov GI, Friedman TB. Actin-bundling protein TRIOBP forms resilient rootlets of hair cell stereocilia essential for hearing. Cell. 2010 May 28;141(5):786-98.
- King KA, Choi BY, Zalewski C, Madeo AC, Manichaikul A, Pryor SP, Ferruggiaro A, Eisenman D, Kim HJ, Niparko J, Thomsen J, Butman JA, Griffith AJ, Brewer CC. SLC26A4 genotype, but not cochlear radiologic structure, is correlated with hearing loss in ears with an enlarged vestibular aqueduct. Laryngoscope. 2010 Feb;120(2):384-9.
- Park HJ, Cho HJ, Baek JI, Ben-Yosef T, Kwon TJ, Griffith AJ, Kim UK. Evidence for a founder mutation causing DFNA5 hearing loss in East Asians. J Hum Genet. 2010 Jan;55(1):59-62. Epub 2009 Nov 13.
- Khan SY, Riazuddin S, Shahzad M, Ahmed N, Zafar AU, Rehman AU, Morell RJ, Griffith AJ, Ahmed ZM, Riazuddin S, Friedman TB. DFNB79: reincarnation of a nonsyndromic deafness locus on chromosome 9q34.3. Eur J Hum Genet. 2010 Jan;18(1):125-9. Epub.
- Makishima T, King K, Brewer CC, Zalewski CK, Butman J, Bakalov VK, Bondy C, Griffith AJ. Otolaryngologic markers for the early diagnosis of Turner syndrome. Int J Pediatr Otorhinolaryngol. 2009 Nov;73(11):1564-7. Epub 2009 Sep 3.
- Choi BY, Stewart AK, Nishimura KK, Cha WJ, Seong MW, Park SS, Kim SW, Chun YS, Chung JW, Park SN, Chang SO, Kim CS, Alper SL, Griffith AJ, Oh SH. Efficient molecular genetic diagnosis of enlarged vestibular aqueducts in East Asians. Genet Test Mol Biomarkers. 2009 Oct;13(5):679-87.
- Madeo AC, Manichaikul A, Reynolds JC, Sarlis NJ, Pryor SP, Shawker TH, Griffith AJ. Evaluation of the thyroid in patients with hearing loss and enlarged vestibular aqueducts. Arch Otolaryngol Head Neck Surg. 2009 Jul;135(7):670-6.
- Choi BY, Madeo AC, King KA, Zalewski CK, Pryor SP, Muskett JA, Nance WE, Butman JA, Brewer CC, Griffith AJ. Segregation of enlarged vestibular aqueducts in families with non-diagnostic SLC26A4 genotypes. J Med Genet. 2009 Dec;46(12):856-61. Epub 2009 Jul 2.
- Madeo AC, Manichaikul A, Pryor SP, Griffith AJ. Do mutations of the Pendred syndrome gene, SLC26A4, confer resistance to asthma and hypertension? J Med Genet. 2009 Jun;46(6):405-6. Epub 2009 Mar 15.
- Anwar S, Riazuddin S, Ahmed ZM, Tasneem S, Ateeq-ul-Jaleel, Khan SY, Griffith AJ, Friedman TB, Riazuddin S. SLC26A4 mutation spectrum associated with DFNB4 deafness and Pendred's syndrome in Pakistanis. J Hum Genet. 2009 May;54(5):266-70. Epub 2009 Mar 13.
- Choi BY, Ahmed ZM, Riazuddin S, Bhinder MA, Shahzad M, Husnain T, Riazuddin S, Griffith AJ, Friedman TB. Identities and frequencies of mutations of the otoferlin gene (OTOF) causing DFNB9 deafness in Pakistan. Clin Genet. 2009 Mar;75(3):237-43.
- Choi BY, Alper SL, Griffith AJ. Response to: The c.-103T>C variant in the 5’-UTR of SLC26A4 gene: a pathogenic mutation or coincidental polymorphism. Hum Mutat. 2009;30:1471. (This was a response to a letter that was written about the next publication in Human Mutation.)
- Choi BY, Stewart AK, Madeo AC, Pryor SP, Lenhard S, Kittles R, Eisenman D, Kim HJ, Niparko J, Thomsen J, Arnos KS, Nance WE, King KA, Zalewski CK, Brewer CC, Shawker T, Reynolds JC, Butman JA, Karniski LP, Alper SL, Griffith AJ. Hypo-functional SLC26A4 variants associated with nonsyndromic hearing loss and enlargement of the vestibular aqueduct: genotype-phenotype correlation or coincidental polymorphisms? Hum Mutat. 2009 Apr;30(4):599-608.
- Hilgert N, Monahan K, Kurima K, Li C, Friedman RA, Griffith AJ, Van Camp G. Amino acid 572 in TMC1: hot spot or critical functional residue for dominant mutations causing hearing impairment. J Hum Genet. 2009 Mar;54(3):188-90. Epub 2009 Jan 30.