Mutations in Only One MeCP2 Protein Form Leads to Milder Rett Symptoms in Boy, Report Indicates

Ana Pena, PhD avatar

by Ana Pena, PhD |

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MeCP2 protein

Mutations that affect a specific form of the MeCP2 protein may lead to milder symptoms of Rett syndrome in males, the case report of a 9-year-old boy suggests.

The study, “MeCP2_e2 partially compensates for lack of MeCP2_e1: A male case of Rett syndrome,” was published in the journal Molecular Genetics & Molecular Medicine.

Rett syndrome is almost always caused by mutations in the MECP2 gene. That gene gives instructions for making the MeCP2 protein, which plays important roles in nerve cell function and communication.

As MECP2 is located on the X chromosome, the disorder affects mostly girls.  However, because males have only one X chromosome, an alteration in MECP2 is not compensated by production of normal protein in the other chromosome. That is why the disease was recognized initially only in females and thought to be lethal in males.

Yet, here have been reports of males with Rett syndrome. Typically, these patients have more severe symptoms that develop earlier, beginning at birth or shortly after.

A few specific biological processes can explain why some males with Rett survive. One is mosaicism, which refers to the presence of different groups of cells in the body that are genetically distinct.

In the case of males with Rett, this means that the MECP2 gene is altered in some cells, while in others the gene copy is normal. This happens when a mutation appears during embryonic development. As each cell gives rise to many more cells, the earlier the mutation occurs during development means more cells will have the alteration.

The severity of the disease depends on the percentage of affected cells — the more cells with mutated MECP2 gene the more severe the symptoms.

Researchers described the case of a 9-year-old boy, seen at Asahikawa Medical University in Japan, who had typical Rett symptoms, but whose symptoms were unusually mild for a male. He developed normally until about age 2, but his development began to regress thereafter. At age 3 he was diagnosed with autism spectrum disorder and intellectual disability. Over time, he lost previously acquired skills, including purposeful hand movements, and acquired stereotypic movements (repetitive, purposeless movements) such as hand wringing. At age 6, he lost the ability to speak, and showed unsteady gait and more evident microcephaly (smaller head than normal). At age 7 he also developed epilepsy, which was controlled by treatment with anticonvulsants (carbamazepine and topiramate).Metabolic disorders and other brain alterations were ruled out. Conventional genetic testing failed to identify mutations in the MECP2 gene. However, a more advanced and sensitive technology, called whole-exome sequencing, identified a novel mutation (c.31G>T) in exon 1 of this gene. (Exons are tiny bits of DNA with information to produce proteins.)This variation occurred in about 28% of the child’s blood cells, with most of the produced MeCP2 protein having a normal sequence.

The boy had milder symptoms compared with prior cases of males with similar levels of mutated cells. While the median age at Rett onset was 13 months in previous cases, developmental problems in this boy did not emerge until age 2. At age 9 he was able to walk independently. Only three of six previously reported patients showed this ability.

More tests confirmed that neither of his parents was a carrier of the mutation, indicating it was acquired during the boy’s development.

Researchers believe the difference may lie in the type of genetic mutations underlying the disease. The MECP2 gene naturally codes for two different versions of the MeCP2 protein, called MeCP2_e1 and MeCP2_e2. While the variants in the other patients stopped production of both protein forms, only MeCP2_e1 was affected in the newly described patient. Patients with problems in MeCP2_e1 only are rare, but impairments in MeCP2_e2 only have never been identified.
This suggests that “MeCP2_e2 does not have an essential function in the brain,” and that “even a mild reduction of MeCP2_e1 [in this case in 28% of cells] is sufficient to cause RTT [Rett],” the scientists wrote.” In conclusion, this study is the first to present clinical and molecular evidence that MeCP2_e2 may partially compensate for the deficiency of MeCP2_e1, although further functional studies are needed,” they added.