ANKLE2 – ANKLE2-related Autosomal Recessive Primary Microcephaly

Autosomal recessive primary microcephaly (MCPH) is characterized by reduced brain size at birth and varying degrees of intellectual disability. ANKLE2 encodes a nuclear envelope protein involved in mitotic progression and chromatin organization. Pathogenic variants in ANKLE2 disrupt normal neurogenesis, leading to microcephaly with additional structural brain anomalies.

In a cohort of 12 unrelated individuals with congenital or postnatal microcephaly and intellectual disability, biallelic ANKLE2 variants were identified by whole-exome sequencing (PMID:35871307). All probands exhibited z-scores ≤–3 for head circumference, consistent with autosomal recessive inheritance and full penetrance. Parental segregation was consistent with trans configuration, although no additional affected relatives were reported.

The variant spectrum includes loss-of-function and missense alleles. Reported mutations comprise nonsense and frameshift alleles such as c.706C>T (p.Arg236Ter) and missense changes including c.1606C>T (p.Arg536Cys) and c.687G>C (p.Val229Gly) (PMID:35871307). No recurrent founder mutations have been described to date.

Functional interrogation in Drosophila melanogaster of four ANKLE2 variants demonstrated that p.Arg236Ter and the c.1>C splicing variant act as strong loss-of-function alleles, while p.Val229Gly and p.Arg536Cys retain partial activity, recapitulating the human microcephaly phenotype (PMID:35871307).

A zebrafish ankle2−/− model exhibited reduced brain volume and decreased radial glial progenitor cell counts. Notably, vrk1 knockdown or heterozygous deletion rescued both microcephaly and neurogenic defects, highlighting a conserved ANKLE2–VRK1–BAF pathway in neurodevelopment (PMID:35940133).

Taken together, the genetic identification of 12 probands with biallelic ANKLE2 variants and concordant in vivo functional models establish a strong gene–disease association. The mechanism involves loss of ANKLE2 function leading to impaired neuronal progenitor proliferation via dysregulated BAF phosphorylation. This evidence supports clinical genetic testing of ANKLE2 in individuals with primary microcephaly.

Key Take-home: Biallelic loss-of-function and hypomorphic ANKLE2 variants cause autosomal recessive primary microcephaly, with robust functional validation in fly and zebrafish models informing diagnostic and mechanistic insights.

References

• Annals of clinical and translational neurology • 2022 • ANKLE2-related microcephaly: A variable microcephaly syndrome resembling Zika infection. PMID:35871307
• Biochemical and biophysical research communications • 2022 • Ankle2 deficiency-associated microcephaly and spermatogenesis defects in zebrafish are alleviated by heterozygous deletion of vrk1. PMID:35940133

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