Mutation screening and association analysis of six candidate genes for autism on chromosome 7q

Abstract

Genetic studies have provided evidence for an autism susceptibility locus (AUTS1) on chromosome 7q. Screening for mutations in six genes mapping to 7q, CUTL1, SRPK2, SYPL, LAMB1, NRCAM and PTPRZ1 in 48 unrelated individuals with autism led to the identification of several new coding variants in the genes CUTL1, LAMB1 and PTPRZ1. Analysis of genetic variants provided evidence for association with autism for one of the new missense changes identified in LAMB1; this effect was stronger in a subgroup of affected male sibling pair families, implying a possible specific sex-related effect for this variant. Association was also detected for several polymorphisms in the promoter and untranslated region of NRCAM, suggesting that alterations in expression of this gene may be linked to autism susceptibility.

NrCAM in Addiction Vulnerability: Positional Cloning, Drug-Regulation, Haplotype-Specific Expression, and Altered Drug Reward in Knockout Mice

“…The current data are in accord with observations from recently reported studies of autism that describe contributions of 5 0 NrCAM haplotypes to autism (Bonora et al, 2005). These additional observations support the idea that variants found in 5 0 NrCAM haplotypes exert functional impact on the gene and its expression.…”

The genetics of autistic disorders and its clinical relevance: a review of the literature

“…Besides LAMB1, the neuronal cell adhesion molecule (NRCAM) gene was assessed in both studies as well. The positive finding in the ASP, however, was again not replicated in the singleton IMGSAC sample, 184 and no association was found for variants in the NRCAM gene in the second study. 185 Taken together, LAMB1 remains an interesting candidate gene for AD, as LAMB1 encodes for the b1 chain of laminin, which is an important glycoprotein promoting neuronal migration and neurite outgrowth in the developing nervous system.…”

“…A novel missense variant (4975C > T = I1547T) in exon 30, which was predicted to have a damaging effect on protein structure, was associated with AD in an affected sib-pair (ASP) sample, but only marginally in the singleton replication sample of the IMGSAC consortium. 184 Another Assessment of the ADOS-G in the AGRE sample is only mentioned in a summary publication on the sample (Gschwind et al 268 ), but not in the publications cited in Table 1.…”

“…186,187 Variants in the protein-tyrosine phosphatase, receptor-type, zeta-1 (PTPRZ1) gene, which is highly expressed in the brain during embryogenesis, 188 have been assessed by two studies. 171,184 No association with AD was found.…”

Molecular genetics of addiction vulnerability

“…Further, recent reports document association of NrCAM 5= haplotypes with one of the prototypical disorders of mnemonic and cognitive systems, autism. These associations have been made in one sample with markers for the same haplotype that are independent of the ones that we have employed in our studies and in another study examining autism subjects versus control subjects using the same markers employed in our studies (see 40 ; T Sakurai et al, personal communication). Thus, there is relatively strong support for the idea that these NrCAM variants can exert plieotropic effects on addiction relevant and mnemonic/cognitive systems in humans and in animal models.…”