X-linked mental retardation syndrome with short stature, small hands and feet, seizures, cleft palate, and glaucoma is linked to Xq28

Abstract

Of the gene-rich regions of the human genome, Xq28 is the most densely mapped. Mutations of genes in this band are responsible for 10 syndromal forms of mental retardation and 5 nonsyndromal forms. Clinical and molecular studies reported here add an additional syndromic form of X-linked mental retardation (XLMR) to this region. The condition comprises short stature, small hands and feet, seizures, cleft palate, and glaucoma. One affected male died at age 19 years in status epilepticus, but others have survived to old age. Carrier females do not have somatic anomalies or mental impairment. The gene is localized to the terminal 8 Mb of Xq28 with markers distal to DXS8011 showing linkage to the disorder with a lod score of 2.11 at zero recombination.

Role of Rab GDP dissociation inhibitor α in regulating plasticity of hippocampal neurotransmission

“…Moreover, Rab GDI␣ might be linked to inhibition of epileptic seizures because mutations in the distal part of chromosome Xq28 containing the Rab GDI␣ gene are likely to lead to syndromic XLMR that comprises anomalies of stature and epileptic seizures (13). In our animal model, the electrical activity associated with epileptic seizures was clearly detected in the Rab GDI␣-deficient mice, which was more susceptible to bicuculline than the wild-type mice.…”

“…Rab GDI␣ function is required for the development of normal intelligence, but it might be linked to inhibition of epilepsy, because mutations of the Rab GDI␣ gene are likely to lead to syndromic XLMR associated with epileptic seizures (13). Thus, it is conceivable that changes in the firing properties of Rab GDI␣-deficient neurons would make this hyperexcitable state vulnerable to epileptic seizures.…”

“…Genetic analysis of X-linked nonspecific mental retardation (XLMR) has revealed that mutations of the Rab GDI␣ gene can cause this disease (11). It is of note that Rab GDI␣ is localized to the distal part of chromosome Xq28 (12), because genetic defects mapped in this region have recently been described to cause a syndromic form of XLMR that comprises epileptic seizures (13). These observations suggest that Rab GDI␣ has a specialized function of the neuronal cells that may be related to suppress hyperexcitability.…”

A New Functional Domain of Guanine Nucleotide Dissociation Inhibitor (α‐GDI) Involved in Rab Recycling

“…Thus, it may be necessary to localize a-GDI via a Rab3A-independent mechanism to the fusion site to coordinate the rapid events triggering GTP hydrolysis with neurotransmitter release and retrieval of Rab-GDP. The importance of a-GDI at the synapse is underscored by the fact that loss of a-GDI function leads to non-syndromic X-linked mental retardation (XLMR) (28) and, potentially, syndromic-XLMR (29). Our results raise the possibility that a-GDI control of Rab3A levels on synaptic membranes may play a heretofore unappreciated role in regulating synapse function in transmitter release and in neural development.…”

Primary ovarian failure in a mentally retarded woman with a de novo unbalanced X;autosome translocation

“…The critical regions of Xq13-q22 and Xq22-q27 are characteristically associated with gonadal dysgenesis, and the Xq28 region is believed to contain more than four X-linked mental retardation genes (14). The clinical presentation of abnormal ovarian activity and mental retardation is consistent with the positional effect of the loss of genetic material in the Xq27-qter segment.…”