Golabi-Ito-Hall syndrome results from a missense mutation in the WW domain of the PQBP1 gene

Background: Golabi, Ito, and Hall reported a family with X linked
mental retardation (XLMR), microcephaly, postnatal growth
deficiency, and other anomalies, including atrial septal defect, in
1984.Methods: This family was restudied as part of our ongoing
study of XLMR, but significant linkage to X chromosome markers
could not be found. Extreme short stature and microcephaly as well
as other new clinical findings were observed. Mutations in the
polyglutamine tract binding protein 1 gene (PQBP1) have recently
been reported in four XLMR disorders (Renpenning, Hamel
cerebro-palato-cardiac, Sutherland-Haan, and Porteous syndromes) as
well as in several other families. The clinical similarity of our
family to these patients with mutations in PQBP1, particularly the
presence of microcephaly, short stature, and atrial septal defect,
prompted examination of this gene.Results: A missense mutation in
PQBP1 was identified which changed the conserved tyrosine residue
in the WW domain at position 65 to a cysteine (p.Y65C).Conclusions:
This is the first missense mutation identified in PQBP1 and the
first mutation in the WW domain of the gene. The WW domain has been
shown to play an important role in the regulation of transcription
by interacting with the PPxY motif found in transcription factors.
The p.Y65C mutation may affect the proper functioning of the PQBP1
protein as a transcriptional co-activator.