Progranulin mutations in primary progressive aphasia: the PPA1 and PPA3 families.
BACKGROUND
Primary progressive aphasia (PPA) is a language-based dementia characterized by fluent or nonfluent language disorder as its principal feature.


OBJECTIVE
To describe progranulin gene mutations in 2 families with PPA.


METHODS
Report of affected families.


METHODS
Academic research.


METHODS
Two families, PPA1 and PPA3, were studied. Genomic DNA was isolated from 3 of 4 siblings in PPA1, from all 3 siblings in PPA3, and from more than 200 control subjects.


METHODS
All 12 coding exons of the progranulin gene and the 5" and 3" untranslated regions were amplified by polymerase chain reaction and were sequenced in both directions using relevant primers.


RESULTS
Both affected members of PPA1 for whom DNA was available and both affected sisters of PPA3 had a progranulin gene mutation not found in the unaffected siblings or in the controls. The mutations likely cause a null allele and a reduction in the level of functional progranulin protein. Both affected members of PPA1 with autopsies had frontotemporal lobar degeneration with tau-negative ubiquinated inclusions.


CONCLUSIONS
To our knowledge, these are the only known families in which affected members display phenotypical homogeneity for PPA in the initial stages of the disease. In both families, the disease segregated with progranulin gene mutations. Whether progranulin dysfunction also extends to sporadic PPA and how it affects the initial anatomical specificity of neurodegeneration remain to be determined.
Mesulam
Marsel
M
Cognitive Neurology and Alzheimer's Disease Center and Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Ill 60611, USA. mmesulam@northwestern.edu
Johnson
Nancy
N
Krefft
Thomas A
TA
Gass
Jennifer M
JM
Cannon
Ashley D
AD
Adamson
Jennifer L
JL
Bigio
Eileen H
EH
Weintraub
Sandra
S
Dickson
Dennis W
DW
Hutton
Michael L
ML
Graff-Radford
Neill R
NR
D000368:Aged; D000369:Aged, 80 and over; D018888:Aphasia, Primary Progressive / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis / Q000379:methods; D005192:Family Health; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D036341:Intercellular Signaling Peptides and Proteins / Q000145:classification / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D000077153:Progranulins; D025801:Ubiquitin / Q000378:metabolism
C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D025801:Ubiquitin