MRX87 family with Aristaless X dup24bp mutation and implication for polyAlanine expansions.
BACKGROUND
Cognitive impairments are heterogeneous conditions, and it is estimated that 10% may be caused by a defect of mental function genes on the X chromosome. One of those genes is Aristaless related homeobox (ARX) encoding a polyA-rich homeobox transcription factor essential for cerebral patterning and its mutations cause different neurologic disorders. We reported on the clinical and genetic analysis of an Italian family with X-linked mental retardation (XLMR) and intra-familial heterogeneity, and provided insight into its molecular defect.


METHODS
We carried out on linkage-candidate gene studies in a new MRX family (MRX87). All coding regions and exon-intron boundaries of ARX gene were analysed by direct sequencing.


RESULTS
MRX87 patients had moderate to profound cognition impairment and a combination of minor congenital anomalies. The disease locus, MRX87, was mapped between DXS7104 and DXS1214, placing it in Xp22-p21 interval, a hot spot region for mental handicap. An in frame duplication of 24 bp (ARXdup24) in the second polyAlanine tract (polyA_II) in ARX was identified.


CONCLUSIONS
Our study underlines the role of ARXdup24 as a critical mutational site causing mental retardation linked to Xp22. Phenotypic heterogeneity of MRX87 patients represents a new observation relevant to the functional consequences of polyAlanine expansions enriching the puzzling complexity of ARXdup24-linked diseases.
Laperuta
Carmela
C
Institute of Genetics and Biophysics Adriano Buzzati Traverso CNR, Naples, Italy. laperuta@igb.cnr.it
Spizzichino
Letizia
L
D'Adamo
Pio
P
Monfregola
Jlenia
J
Maiorino
Antonio
A
D'Eustacchio
Angela
A
Ventruto
Valerio
V
Neri
Giovanni
G
D'Urso
Michele
M
Chiurazzi
Pietro
P
Ursini
Matilde Valeria
MV
Miano
Maria Giuseppina
MG
D041321:Chromosomes, Human, X; D017931:DNA Primers; D020440:Gene Duplication; D008040:Genetic Linkage; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010455:Peptides / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*
C469264:ARX protein, human; D017931:DNA Primers; D018398:Homeodomain Proteins; D010455:Peptides; D014157:Transcription Factors; C019529:polyalanine