Publications

Abstract

Individuals affected with developmental disorders of speech and language have substantial difficulty acquiring expressive and/or receptive language in the absence of any profound sensory or neurological impairment and despite adequate intelligence and opportunity. Although studies of twins consistently indicate that a significant genetic component is involved, most families segregating speech and language deficits show complex patterns of inheritance, and a gene that predisposes individuals to such disorders has not been identified. We have studied a unique three-generation pedigree, KE, in which a severe speech and language disorder is transmitted as an autosomal-dominant monogenic trait. Our previous work mapped the locus responsible, SPCH1, to a 5.6-cM interval of region 7q31 on chromosome 7 (ref. 5). We also identified an unrelated individual, CS, in whom speech and language impairment is associated with a chromosomal translocation involving the SPCH1 interval. Here we show that the gene FOXP2, which encodes a putative transcription factor containing a polyglutamine tract and a forkhead DNA-binding domain, is directly disrupted by the translocation breakpoint in CS. In addition, we identify a point mutation in affected members of the KE family that alters an invariant amino-acid residue in the forkhead domain. Our findings suggest that FOXP2 is involved in the developmental process that culminates in speech and language

Abstract

Leprosy, a chronic infectious disease caused by Mycobacterium leprae, is prevalent in India, where about half of the world's estimated 800,000 cases occur. A role for the genetics of the host in variable susceptibility to leprosy has been indicated by familial clustering, twin studies, complex segregation analyses and human leukocyte antigen (HLA) association studies. We report here a genetic linkage scan of the genomes of 224 families from South India, containing 245 independent affected sibpairs with leprosy, mainly of the paucibacillary type. In a two-stage genome screen using 396 microsatellite markers, we found significant linkage (maximum lod score (MLS) = 4.09, P < 2x10-5) on chromosome 10p13 for a series of neighboring microsatellite markers, providing evidence for a major locus for this prevalent infectious disease. Thus, despite the polygenic nature of infectious disease susceptibility, some major, non-HLA-linked loci exist that may be mapped through obtainable numbers of affected sibling pairs.