Miller-Dieker syndrome (MDS) is caused by a heterozygous deletion of chromosome 17p13.3 involving the genes LIS1 and YWHAE (coding for 14.3.3ε) and leads to malformations during cortical development.
14-3-3ε, encoded by YWHAE, is an adapter protein belonging to the 14-3-3 protein family which plays important roles in neuronal development and is involved in Miller-Dieker syndrome.
Examination of cerebral spinal fluid in humans suggests that 14-3-3s including 14-3-3ε (YWHAE) are up-regulated in several neurological diseases, and loss or duplication of the YWHAE gene leads to Miller-Dieker syndrome.
Deletions of the PAFAH1B1 gene (encoding LIS1) in 17p13.3 result in isolated lissencephaly sequence, and extended deletions including the YWHAE gene (encoding 14-3-3epsilon) cause Miller-Dieker syndrome.
Six different genes could be responsible for this entity (LIS1, DCX, TUBA1A, VLDLR, ARX, RELN), although co-delection of YWHAE gene with LIS1 could result in Miller-Dieker Syndrome.
Point mutations or deletion copy number variants of the PAFAH1B1 gene in this genomic region cause lissencephaly, whereas extended deletions involving both PAFAH1B1 and YWHAE result in Miller-Dieker syndrome characterised by facial dysmorphisms and a more severe grade of lissencephaly.
Microdeletions including YWHAE in the Miller-Dieker syndrome region on chromosome 17p13.3 result in facial dysmorphisms, growth restriction, and cognitive impairment.
PAFAH1B1/LIS1 and YWHAE, which were deleted in isolated lissencephaly (PAFAH1B1/LIS1 alone) and Miller-Dieker syndrome (both genes), were found to be duplicated in patients with developmental delay.
We have created a physical map covering approximately 3.5 Mb (6 cM)in this region, spanning the RP13 interval and extending distally to the gene MDCR (formerly, LIS1), which, when deleted, leads to the MDLS phenotype.