national institute on deafness and other communication disorders (nidcd) u.s. department of health...
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National Institute on Deafness and Other Communication Disorders (NIDCD)
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutesof Health
Discovery of Causes of Stuttering
Dennis Drayna, PhDJuly 8, 2010
• Twin studies– Heritability estimates range from 50-70%
• Adoption studies– No evidence that stuttering is learned
• Family clusters of stuttering– Many small and a few large families
• Segregation analysis– Less successful
Evidence for genetic factors in stuttering
Research plan
• Begin with genetic linkage studies– Applicable to any inherited disorder• Don’t need to know anything about the
underlying cause
– Identify the location of the gene or genes that cause the disorder• Genes reside on structures inside cells called
chromosomes – which chromosome?
– Performed in families
North American linkage study
• Studied 70 modest sized nuclear families
• Found weak evidence of linkage on chromosome 18
• Conclusion - there is no single common gene that causes stuttering in the general North American population
Similar results from studies by others
• Suggestive evidence for linkage on chromosomes 2, 3, 5, 7, 9, 12, 13, 15, and 21
• Typical of linkage results for human complex traits– Weak support for the findings– Failures to find the same location across studies– No direct identification of disease genes
Advantageous population structure—Pakistan
• 70% of all marriages between either 1st or 2nd cousins
• This marriage pattern has persisted over centuries
• Results in a population structure with greatly increased incidence of genetic disorders
Finding stuttering families in Pakistan
• Collaborated with the National Centre of Excellence in Molecular Biology (CEMB), University of Punjab, Lahore
• Sought stuttering families through the school system
• Identified 100 families, chose 44 for our linkage study
Gene identification strategy
• Focus on this region on chromosome 12 in Pakistani family PKST72
• 87 genes lie within this interval
Variant of interest
• Variant that went along with stuttering in family PKST72 and did not appear in the normal Pakistani population
• This variant was an apparent mutation in a gene called GNPTAB
• This mutation changes an important part of the gene– Invariant across all species known
Mutation associated with stuttering in family PKST72
• The same mutation occurs in affected individuals in Pakistani families PKST 05, 25, 41– 4/41 families suggests this mutation could
account for ~10% of stuttering families in Pakistan
• The same mutation occurs in unrelated people who stutter from Pakistan and India
• Mutation not observed in normal North American individuals
Three other mutations in GNPTAB identified
• Found in affected individuals of South Asian and European descent
• All are mutations that make a change at a place in the gene an important place in the gene
• None ever found in normal control individuals
GNPTAB
• Encodes part of an enzyme
• Enzyme involved in the normal metabolism of all cells
• Functions as part of the cell’s “recycling bin”
GNPTG
• Encodes another part of the same enzyme
• Identified 3 different mutations in 4 unrelated affected individuals
• All affect important parts of the gene
• All not observed in normals
GNPTAB/G
• Performs the first step in the lysosomal targeting pathway, which is responsible for directing ~ 60 enzymes to the cell’s “recycling bin”, known as the lysosome
NAGPAThe uncovering enzyme
• Performs the next step in the lysosomal targeting pathway
• Identified 3 mutations in 6 unrelated individuals– All of European descent
• All affect important parts of the enzyme
• None observed in normal control individuals
GNPTAB/G mutations in known disorders
• Mutations in GNPTAB and GNPTG are known to cause mucolipidosis II and III (ML II and ML III)
• MLII is a severe disorder, fatal in the first decade of life
• MLIII is a less serious disease
• Both are rare lysosomal storage disorders with primary problems displayed in the skeletal system, joints, brain, liver, spleen
NAGPA mutations?
• No disorder in humans has been associated with NAGPA mutations
• This is surprising, because these might be expected to result in medical symptoms similar to those observed in ML II and III
• We hypothesize that the primary manifestation of NAGPA mutations is persistent stuttering
Discussion
• Mutations in these 3 genes may account for 5-10% of familial stuttering worldwide, and stuttering in more than 100,000 individuals in the U.S. alone
• Lysosomal targeting disorders are clearly no longer rare
• Indicates that stuttering now overlaps the field of medicine
• Enzyme replacement therapy for lysosomal storage disorders is now well established
Is stuttering a mild form of mucolipidosis?
• To date, we’ve examined 4 affected individuals at the NIH Clinical Center
• No symptoms of ML II or ML III were observed in any of these individuals
• Other than stuttering, all 4 individuals were neurologically normal
Implications for Speech Language Pathology • Our results explain a small fraction
of stuttering• Our results will allow us to ask
questions about therapy– Could underlying genetic differences
explain differences in therapy outcomes?
• Our results suggest a coming partnership between SLPs and physicians
Working hypothesis
• A specific group of nerve cells in the brain are unique to speech production and also uniquely sensitive to this metabolic deficit
• Goal – Identify these cells, discover what they do, determine what they’re connected to, and understand how this inherited deficit uniquely affects them
Acknowledgments• NIDCD
– Changsoo Kang – M. Hashim Raza– Naveeda Riaz– Eduardo Sainz– Joe Kleinman– Alison Fedyna
• NHGRI/NISC– Alice Young– Jim Mullikan– Donna Krasnewich
• NIH Clinical Center– Penelope Friedman
• NCBI– Alejandro Schaffer
• Hollins Communications Research Institute– Jennifer Mundorff
• CEMB/University of the Punjab– Jamil Ahmad– Shahid Khan– S. Riazuddin
• Stuttering Foundation of America
• British Stammering Association• National Stuttering Association• Speak Clear Association of
Cameroon– Joseph Lukong
• Stuttering research subjects worldwide