A 2‐Mb critical region implicated in the microcephaly associated with terminal 1q deletion syndrome

Abstract

Patients with distal deletions of chromosome 1q have a recognizable syndrome that includes microcephaly, hypoplasia or agenesis of the corpus callosum, and psychomotor retardation. Although these symptoms have been attributed to deletions of 1q42-1q44, the minimal chromosomal region involved has not been identified. Using microsatellite and single nucleotide polymorphism (SNP) markers, we have mapped the deleted regions in seven patients with terminal deletions of chromosome 1q to define a 2.0-Mb microcephaly critical region including the 1q43-1q44 boundary and no more than 11 genes.

RP58/ZNF238 directly modulates proneurogenic gene levels and is required for neuronal differentiation and brain expansion

“…Critically, loss of RP58 in the CNS leads to a novel postnatal small-brain phenotype with loss of corpus callosum and cerebellar vermis hypoplasia, which resembles the human microencephaly phenotype linked to loss of chromosome-1qter. [9][10][11][12] Defective organization of the cerebral cortex in RP58 mutants. In order to confirm and extend the reported localization of RP58 in the mouse brain 15 and to interpret correctly the phenotypes described above, we performed antisense RNA in situ hybridization analyses on sections of mouse brains at different stages of development.…”

“…Interestingly, deletion of the distal end of human chromosome-1q is linked to microcephaly with agenesis of the corpus callosum (e.g. [9][10][11], and a critical region contains only a handful of genes, including RP58. 9-12 RP58, also known as ZNF238, 13 encodes a transcription factor with a BTB/POZ and four zincfinger domains 14 that is highly conserved (495%) between humans and mice, suggesting conserved functions.…”

Subtelomeric deletions of 1q43q44 and severe brain impairment associated with delayed myelination

“…4,6,7,9,11,18 After chromosomal microarray testing has been available for the identification of submicroscopic chromosomal aberrations, many patients with submicroscopic deletions of 1q44 have been identified. 8,10,12,14,15 Now, precise genotype-phenotype correlation has been evaluated through the accumulation of patients with variable deletion sizes, and a minimal essential region has been proposed for expressing the main characteristics of 1q44 deletion syndrome. 7,8,[14][15][16] Ballif et al 17 evaluated 22 patients with small interstitial deletions of 1q44 and demonstrated critical regions for microcephaly, ACC and seizures.…”

“…8,10,12,14,15 Now, precise genotype-phenotype correlation has been evaluated through the accumulation of patients with variable deletion sizes, and a minimal essential region has been proposed for expressing the main characteristics of 1q44 deletion syndrome. 7,8,[14][15][16] Ballif et al 17 evaluated 22 patients with small interstitial deletions of 1q44 and demonstrated critical regions for microcephaly, ACC and seizures. Consequently, AKT3 was reported to be the gene responsible for microcephaly; zinc finger protein 238 gene (ZNF238) for ACC; and heterogeneous nuclear ribonucleoprotein U gene (HNRNPU) for seizures 17 ( Figure 5).…”

“…3 Several studies have investigated the critical region for 1q44 subtelomeric deletion syndrome and found that the core phenotypic features of 1q44 subtelomeric deletion syndrome are microcephaly, abnormalities of the corpus callosum (ACC) and seizures. [4][5][6][7][8][9][10][11][12][13][14][15][16] Recently, Ballif et al 17 analyzed patients with microdeletions of 1q44 and proposed certain genes that may be responsible for individual features.…”