A mutation in the rett syndrome gene, MECP2, causes X-linked mental retardation and progressive spasticity in males - PubMed (original) (raw)

A mutation in the rett syndrome gene, MECP2, causes X-linked mental retardation and progressive spasticity in males

I Meloni et al. Am J Hum Genet. 2000 Oct.

Abstract

Heterozygous mutations in the X-linked MECP2 gene cause Rett syndrome, a severe neurodevelopmental disorder of young females. Only one male presenting an MECP2 mutation has been reported; he survived only to age 1 year, suggesting that mutations in MECP2 are male lethal. Here we report a three-generation family in which two affected males showed severe mental retardation and progressive spasticity, previously mapped in Xq27.2-qter. Two obligate carrier females showed either normal or borderline intelligence, simulating an X-linked recessive trait. The two males and the two obligate carrier females presented a mutation in the MECP2 gene, demonstrating that, in males, MECP2 can be responsible for severe mental retardation associated with neurological disorders.

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Figures

Figure 1

Figure 1

Segregation of the mutation in the family; 3% agarose gel of _Avr_II-digested PCR products of segment D of exon 3 (396 bp) obtained as reported elsewhere (De Bona et al. 2000). The C→T transition in position 1216 creates the “ccTagg” _Avr_II restriction site from the normal “cccagg” sequence, generating two fragments of 213 and 183 bp. Line 1, molecular weight marker VI (Roche), following lines as reported in pedigree above; ND = nondigested control.

Figure 2

Figure 2

Quantitative RT-PCR of total RNA from lymphoblastoid cells of patient (OE) and male (XY) and female (XX) controls. Primers were MECP-2 RT-S: 5′-CGC TCC ATC ATC CGT GAC-3′; MECP-2 RS-A: 5′-TCT GCC AGT TCC TGG AGC-3′; GAPDH-F: 5′-AAC ACA GTC CAT GCC ATC AC-3′; GAPDH-R: 5′-TCC ACC ACC CTG TTG CTG TA-3′. The RT was done with (+) and without (−) retrotranscriptase, as described elsewhere (Bione et al. 1996), using 1 μg of total RNA. We amplified 2.5 μl of the RT reaction in a 50-μl PCR reaction. C = PCR control without template DNA. PCR conditions were the following: GAPDH: 5 min at 94°C; 30 s at 94°C, 30 s at 60°C, and 30 s at 72°C for 25 cycles; MECP-2: 5 min at 94°C; 30 s at 94°C, 30 s at 60°C, and 30 s at 72°C for 35 cycles.

Figure 3

Figure 3

Results of X-inactivation assay: 6% polyacrylamide silver-stained gel of PCR product of CAG repeat of the androgen-receptor gene (Allen et al. 1992) from _Hpa_II digested (D) and nondigested (ND) DNA of the carrier females. Primers used for PCR amplification were RS-6: 5′-GTC CAA GAC CTA CCG AGG AG-3′ and RS-7: 5′-CCA GGA CCA GGT AGC CTG TG-3′. Band intensities were measured by Diversity Database program (Biorad), and the values were corrected for preferential allele amplification (Pegoraro et al. 1994). Results showed a balanced X-inactivation: ∼56% of X-bearing allele b active (b) and 44% of X-bearing allele a active (a) in the mother (right panel); ∼60% of normal paternal X active (c) and 40% of mutated X active (a) in the daughter (left panel).

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References

Electronic-Database Information

    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for the MECP2 gene [MIM <300005>] and Rett syndrome [MIM <312750>])

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