XLMR in MRX families 29, 32, 33 and 38 results from the dup24 mutation in the ARX (Aristaless related homeobox) gene

Monica L Stepp,Jozef Gecz,Elke Holinski-Feder,A Lauren Cason,Roger E Stevenson,Merran Finnis,Jeanette Ja Holden,Charles E Schwartz,Marie Mangelsdorf,David Macgregor,Andrée Macmillan

doi:10.1186/1471-2350-6-16

Abstract

BackgroundX-linked mental retardation (XLMR) is the leading cause of mental retardation in males. Mutations in the ARX gene in Xp22.1 have been found in numerous families with both nonsyndromic and syndromic XLMR. The most frequent mutation in this gene is a 24 bp duplication in exon 2. Based on this fact, a panel of XLMR families linked to Xp22 was tested for this particular ARX mutation.MethodsGenomic DNA from XLMR families linked to Xp22.1 was amplified for exon 2 in ARX using a Cy5 labeled primer pair. The resulting amplicons were sized using the ALFexpress automated sequencer.ResultsA panel of 11 families with X-linked mental retardation was screened for the ARX 24dup mutation. Four nonsyndromic XLMR families – MRX29, MRX32, MRX33 and MRX38 – were found to have this particular gene mutation.ConclusionWe have identified 4 additional XLMR families with the ARX dup24 mutation from a panel of 11 XLMR families linked to Xp22.1. This finding makes the ARX dup24 mutation the most common mutation in nonsyndromic XLMR families linked to Xp22.1. As this mutation can be readily tested for using an automated sequencer, screening should be considered for any male with nonsyndromic MR of unknown etiology.

Highlights

X-linked mental retardation (XLMR) is the leading cause of mental retardation in males
We have recently identified the same 24 bp duplication in 4 other nonsyndromic XLMR families linked to Xp22.1: MRX29 [7], MRX32 [8], MRX33 [9], and MRX38 [10]
Genomic DNA from members of eleven XLMR families linked to Xp22.1, a West Syndrome family with a 21 bp insertion [3], two positive controls for the 24 bp duplication [3], and a negative control was amplified by PCR using locus specific primer pairs designed for exon 2 of ARX

Summary

Introduction

X-linked mental retardation (XLMR) is the leading cause of mental retardation in males. The most frequent mutation reported in ARX is an inframe 24 bp duplication in exon 2, which causes an expansion of the polyalanine tract at amino acid positions 144–155, from 12 to 20 alanines. This duplication has been reported in a Norwegian family with West Syndrome [3,4] as well as four published nonsyndromic XLMR families, MRX36 [5], MRX43, MRX54 and MRX76 [6]. We have recently identified the same 24 bp duplication in 4 other nonsyndromic XLMR families linked to Xp22.1: MRX29 [7], MRX32 [8], MRX33 [9], and MRX38 [10]

Methods

Results

Discussion

Conclusion