Maternally and paternally inherited deletion of 7q31 involving the FOXP2 gene in two families

The speech geneFOXP2is not imprinted

“…Together, these findings strongly implicate a differential parent-of-origin expression effect with regard to FOXP2 in the development of human speech. However, a recent report has described two unrelated patients with speech impairment and developmental delay who both display maternal inheritance of a FOXP2 deletion, which casts some doubt on the parental origin idea 11. Given that this level of gene regulation would add a significant and intriguing level of complexity to both its evolutionary origin3 and the regulatory mechanism contributing to the cause of the DVD speech impairment,2 we set out to resolve FOXP2 imprinting at the mRNA expression level.…”

Monoallelic expression of the human FOXP2 speech gene

“…For most genes, it is generally assumed that there is biallelic expression, which would lead, in the case of a hemizygous deletion, to halving the gene dosage in all cells. Before our work, it was known that FOXP2 translocations, deletions, and truncating mutations are disease-causing (37)(38)(39)(40)(41), and thus the presumptive etiology would be "homogeneous" haploinsufficiency wherein all cells express half the normal amount of FOXP2. However, here, we present data indicating that FOXP2 is subject to RMAE.…”

“…Mutations in FOXP2, a forkhead domain-containing transcription factor, are known to cause an autosomal-dominant condition characterized by abnormal development of several brain areas critical for both developmental verbal movements and sequential articulation, with largely incomprehensible speech and marked disruption of multiple aspects of grammar and language (35)(36)(37). Truncating mutations and translocations interrupting the FOXP2 gene sequence are sufficient to cause the phenotype, which has led to the conclusion that haploinsufficiency is the likely etiology; in other words, a single copy of a WT allele is incapable of providing sufficient protein for normal function (38)(39)(40)(41). Thus, haploinsufficiency is different from both a dominant-negative effect wherein a nonfunctional mutant polypeptide interferes with the function of the normal allele, or gain-offunction mutations, wherein a changed gene product is endowed with a new and abnormal function.…”

A Molecular Genetic Perspective on Speech and Language

“…In the reported large-scale deletion cases, one copy of FOXP2 is completely lost from the genome, often together with other flanking genes (Feuk et al, 2006;Lennon et al, 2007;Palka et al, 2012;Rice et al, 2012;Zeesman et al, 2006;Zilina et al, 2012). Investigations of the phenotypes observed in these cases again support the idea that damage to one copy of FOXP2 is sufficient to derail speech and language development, although the larger deletions that encompass multiple other genes are often noted to include additional problems.…”

“…So far, two types of gross chromosomal rearrangements have been reported to affect FOXP2: translocations (Feuk et al, 2006;Kosho et al, 2008;Lai et al, 2001;Shriberg et al, 2006) and deletions (Feuk et al, 2006;Lennon et al, 2007;Palka et al, 2012;Rice et al, 2012;Zeesman et al, 2006;Zilina et al, 2012). In the translocation cases, part of chromosome 7 is exchanged with part of another chromosome; because the chromosome 7 breakpoint in these cases lies directly within (or close to) the FOXP2 locus, this is expected to interfere with the activity of the disrupted copy (Feuk et al, 2006;Kosho et al, 2008;Lai et al, 2001;Shriberg et al, 2006).…”