New insights into genotype–phenotype correlations for the doublecortin-related lissencephaly spectrum

Abstract

X-linked isolated lissencephaly sequence and subcortical band heterotopia are allelic human disorders associated with mutations of doublecortin (DCX), giving both familial and sporadic forms. DCX encodes a microtubule-associated protein involved in neuronal migration during brain development. Structural data show that mutations can fall either in surface residues, likely to impair partner interactions, or in buried residues, likely to impair protein stability. Despite the progress in understanding the molecular basis of these disorders, the prognosis value of the location and impact of individual DCX mutations has largely remained unclear. To clarify this point, we investigated a cohort of 180 patients who were referred with the agyria-pachygyria subcortical band heterotopia spectrum. DCX mutations were identified in 136 individuals. Analysis of the parents' DNA revealed the de novo occurrence of DCX mutations in 76 cases [62 of 70 females screened (88.5%) and 14 of 60 males screened (23%)], whereas in the remaining cases, mutations were inherited from asymptomatic (n = 14) or symptomatic mothers (n = 11). This represents 100% of families screened. Female patients with DCX mutation demonstrated three degrees of clinical-radiological severity: a severe form with a thick band (n = 54), a milder form (n = 24) with either an anterior thin or an intermediate thickness band and asymptomatic carrier females (n = 14) with normal magnetic resonance imaging results. A higher proportion of nonsense and frameshift mutations were identified in patients with de novo mutations. An analysis of predicted effects of missense mutations showed that those destabilizing the structure of the protein were often associated with more severe phenotypes. We identified several severe- and mild-effect mutations affecting surface residues and observed that the substituted amino acid is also critical in determining severity. Recurrent mutations representing 34.5% of all DCX mutations often lead to similar phenotypes, for example, either severe in sporadic subcortical band heterotopia owing to Arg186 mutations or milder in familial cases owing to Arg196 mutations. Taken as a whole, these observations demonstrate that DCX-related disorders are clinically heterogeneous, with severe sporadic and milder familial subcortical band heterotopia, each associated with specific DCX mutations. There is a clear influence of the individual mutated residue and the substituted amino acid in determining phenotype severity.

Different Doublecortin (DCX) Patient Alleles Show Distinct Phenotypes in Cultured Neurons

“…Cortical malformations are recovered in the human populations at a surprisingly high rate and can be familial or arise spontaneously de novo (1)(2)(3)28). One manifestation of cortical malformation is subcortical band heterotopia (SBH) and lissencephaly (LIS; smooth brain).…”

“…A recent extensive study on human patients with SBH found that 100% of familial SBH is caused by mutations in the X-linked gene DCX. For de novo mutations, DCX mutations account for 50 -80% of cases (28). Both DCX-linked SBH (in females) and DCX-linked LIS (in males) are likely caused by neuronal migration defects, but axon outgrowth and guidance defects have also been reported.…”

“…Most strikingly, however, they accumulate spn, a known 6 C. C. Yap, unpublished observations. (28). A subset of DCX alleles might thus cause some excess cell death in patients, but more work will be required to explore this idea.…”

“…We thus used dendrite enhancement by Dcx expression as an assay for wild type Dcx function, using previously described MT binding-competent and MT bindingdeficient mutants (25)(26)(27). All of these alleles were originally identified in patients with lissencephaly (2,28,29). We found that Dcx alleles that retain MT binding but lack the C-terminal regions (required for spn and AP adaptor binding) are defective for dendrite growth promotion (i.e.…”

Novel Mutation chrX:110644366 C>A of the DCX Gene in 4-year-old Girl with Sporadic Double Cortex Syndrome

“…It has been observed that patients with less that 30% mosaicism are clinically unaffected, whereas those with more than 30% of the cells with the mutated allele are symptomatic with SBH. [3] Since the pathogenic mutation has been identified in the family, prenatal testing for pregnancies at increased risk is possible.…”