title: CMIP and ATP2C2 modulate phonological short-term memory in language impairment.
abstract: 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.
authors: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors: Dianne F
authors: DF
authors: Newbury
authors: Laura
authors: L
authors: Winchester
authors: Laura
authors: L
authors: Addis
authors: Silvia
authors: S
authors: Paracchini
authors: Lyn-Louise
authors: LL
authors: Buckingham
authors: Ann
authors: A
authors: Clark
authors: Wendy
authors: W
authors: Cohen
authors: Hilary
authors: H
authors: Cowie
authors: Katharina
authors: K
authors: Dworzynski
authors: Andrea
authors: A
authors: Everitt
authors: Ian M
authors: IM
authors: Goodyer
authors: Elizabeth
authors: E
authors: Hennessy
authors: A David
authors: AD
authors: Kindley
authors: Laura L
authors: LL
authors: Miller
authors: Jamal
authors: J
authors: Nasir
authors: Anne
authors: A
authors: O'Hare
authors: Duncan
authors: D
authors: Shaw
authors: Zoe
authors: Z
authors: Simkin
authors: Emily
authors: E
authors: Simonoff
authors: Vicky
authors: V
authors: Slonims
authors: Jocelynne
authors: J
authors: Watson
authors: Jiannis
authors: J
authors: Ragoussis
authors: Simon E
authors: SE
authors: Fisher
authors: Jonathon R
authors: JR
authors: Seckl
authors: Peter J
authors: PJ
authors: Helms
authors: Patrick F
authors: PF
authors: Bolton
authors: Andrew
authors: A
authors: Pickles
authors: Gina
authors: G
authors: Conti-Ramsden
authors: Gillian
authors: G
authors: Baird
authors: Dorothy V M
authors: DV
authors: Bishop
authors: Anthony P
authors: AP
authors: Monaco
mesh_terms: 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*
chemical_list: 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