CMIP and ATP2C2 modulate phonological short-term memory in language impairment.
Specific language impairment (SLI) is a common developmental disorder characterized by difficulties in language acquisition despite otherwise normal development and in the absence of any obvious explanatory factors. We performed a high-density screen of SLI1, a region of chromosome 16q that shows highly significant and consistent linkage to nonword repetition, a measure of phonological short-term memory that is commonly impaired in SLI. Using two independent language-impaired samples, one family-based (211 families) and another selected from a population cohort on the basis of extreme language measures (490 cases), we detected association to two genes in the SLI1 region: that encoding c-maf-inducing protein (CMIP, minP = 5.5 x 10(-7) at rs6564903) and that encoding calcium-transporting ATPase, type2C, member2 (ATP2C2, minP = 2.0 x 10(-5) at rs11860694). Regression modeling indicated that each of these loci exerts an independent effect upon nonword repetition ability. Despite the consistent findings in language-impaired samples, investigation in a large unselected cohort (n = 3612) did not detect association. We therefore propose that variants in CMIP and ATP2C2 act to modulate phonological short-term memory primarily in the context of language impairment. As such, this investigation supports the hypothesis that some causes of language impairment are distinct from factors that influence normal language variation. This work therefore implicates CMIP and ATP2C2 in the etiology of SLI and provides molecular evidence for the importance of phonological short-term memory in language acquisition.
Newbury
Dianne F
DF
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Winchester
Laura
L
Addis
Laura
L
Paracchini
Silvia
S
Buckingham
Lyn-Louise
LL
Clark
Ann
A
Cohen
Wendy
W
Cowie
Hilary
H
Dworzynski
Katharina
K
Everitt
Andrea
A
Goodyer
Ian M
IM
Hennessy
Elizabeth
E
Kindley
A David
AD
Miller
Laura L
LL
Nasir
Jamal
J
O'Hare
Anne
A
Shaw
Duncan
D
Simkin
Zoe
Z
Simonoff
Emily
E
Slonims
Vicky
V
Watson
Jocelynne
J
Ragoussis
Jiannis
J
Fisher
Simon E
SE
Seckl
Jonathon R
JR
Helms
Peter J
PJ
Bolton
Patrick F
PF
Pickles
Andrew
A
Conti-Ramsden
Gina
G
Baird
Gillian
G
Bishop
Dorothy V M
DV
Monaco
Anthony P
AP
D048868:Adaptor Proteins, Signal Transducing; D000252:Calcium-Transporting ATPases / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D002885:Chromosomes, Human, Pair 16; D015331:Cohort Studies; D008040:Genetic Linkage; D005820:Genetic Testing; D006801:Humans; D007802:Language; D007806:Language Disorders / Q000175:diagnosis / Q000235:genetics*; D008570:Memory, Short-Term; D010700:Phonetics; D051257:Proto-Oncogene Proteins c-maf / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; C540426:CMIP protein, human; D002352:Carrier Proteins; D051257:Proto-Oncogene Proteins c-maf; C452183:ATP2C2 protein, human; D000252:Calcium-Transporting ATPases