Infantile cerebral and cerebellar atrophy is associated with a mutation in the MED17 subunit of the transcription preinitiation mediator complex

Abstract

Primary microcephaly of postnatal onset is a feature of many neurological disorders, mostly associated with mental retardation, seizures, and spasticity, and it typically carries a grave prognosis. Five infants from four unrelated families of Caucasus Jewish origin presented soon after birth with spasticity, epilepsy, and profound psychomotor retardation. Head circumference percentiles declined, and brain MRI disclosed marked cereberal and cerebellar atrophy with severe myelination defect. A search for a common homozygous region revealed a 2.28 Mb genomic segment on chromosome 11 that encompassed 16 protein-coding genes. A missense mutation in one of them, MED17, segregated with the disease state in the families and was carried by four of 79 anonymous Caucasus Jews. A corresponding mutation in the homologous S.cerevisiae gene SRB4 inactivated the protein, according to complementation assays. Screening of MED17 in additional patients with similar clinical and radiologic findings revealed four more patients, all homozygous for the p.L371P mutation and all originating from Caucasus Jewish families. We conclude that the p. L371P mutation in MED17 is a founder mutation in the Caucasus Jewish community and that homozygosity for this mutation is associated with infantile cerebral and cerebellar atrophy with poor myelination.

Figure 1

Brain MRI at 3 Months of Age Coronal (A) and midsagittal (B) T2-weighted magnetic resonance images illustrating pronounced cerebral and cerebellar atrophy.

Figure 2

The c.1112T>C (p.L371P) Mutation in MED17 (A) Exon 7 of MED17. The mutated nucleotide is indicated by an arrow. The patient, an obligate heterozygote, and a control sample are shown in the upper, middle, and lower lanes, respectively. (B) Amino acid conservation at and around the mutated codon (asterisk) site.

Figure 3

SRB4-M504P, Corresponding to Human MED17-L371P, Cannot Complement the Depletion of Active SRB4 in Yeast The wild-type (Z579) and a mutant expressing temperature-sensitive ts-SRB4 (Z628) were transformed with the indicated plasmids. Cultures were serially diluted at 10-fold intervals, and 10 μl of each was spotted onto YPD plates, which were incubated at 25°C (permissive temperature, left panel) or 37°C (restrictive temperature, right panel) for 2 days.