This report describes microcephaly 16, primary, autosomal recessive (MCPH16), which is a subtype of primary microcephaly. The human gene implicated in this disease is Ankyrin Repeat And LEM Domain Containing 2 (ANKLE2), is an inner nuclear membrane protein involved in mitotic nuclear envelope reassembly. There is a single fly ortholog, Ankle2, for which for which classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
A UAS construct of a tagged wild-type Hsap\ANKLE2 gene has been introduced into flies. Heterologous rescue (functional complementation) has been demonstrated for the small brain and lethality phenotypes of homozygous Dmel\Ankle2 mutant animals.
Animals that are homozygous for a loss-of-function allele of Dmel\Ankle2 die prior to adult stage; phenotypes of homozygous third instar larvae include a small brain, increased apoptotic cell death in the brain, and a reduced number of neuroblasts. A small number of physical interactions of Dmel\Ankle2 have been described; see below and in the Ankle2 gene report.
An interaction between the Zika-virus-encoded NS4A protein and human ANKLE2 has been detected. In flies, ubiquitous expression of ZIKV\NS4A in wild-type animals causes a significant decrease in 3rd instar larval brain volume. Expression of either Hsap\ANKLE2 or overexpression of Dmel\Ankle2 rescues this phenotype. Animals heterozygous for a loss-of-function allele of Dmel\Ankle2 have normal larval brain volume; expression of ZIKV\NS4A in these animals results in a severe brain volume reduction. See the human disease model report 'microcephaly, Zika virus-related' (FBhh0001035).
[updated Mar. 2019 by FlyBase; FBrf0222196]
Primary microcephaly (MCPH) refers to the clinical finding of a head circumference less than 3 standard deviations below the age- and sex-related mean, present at birth. Primary microcephaly is a static developmental anomaly, distinguished from secondary microcephaly, which refers to a progressive neurodegenerative condition. Microcephaly is a disorder of fetal brain growth; individuals with microcephaly have small brains and almost always have mental retardation; additional clinical features may include short stature or mild seizures (review by Woods et al., 2005; pubmed:15806441). [from MIM:251200; 2016.06.16]
[MICROCEPHALY 16, PRIMARY, AUTOSOMAL RECESSIVE; MCPH16](https://omim.org/entry/616681)
[ANKYRIN REPEAT- AND LEM DOMAIN-CONTAINING PROTEIN 2; ANKLE2](https://omim.org/entry/616062)
See general description of primary microcephaly, above.
MCPH16 is caused by compound heterozygous mutation in the ANKLE2 gene. [from MIM:616681; 2016.06.16]
ANKLE2 (Ankyrin Repeat And LEM Domain Containing 2) is an inner nuclear membrane protein involved in mitotic nuclear envelope reassembly. [from Gene Cards, ANKLE2; 2106.06.20]
ANKLE2 plays a critical role in reassembly of the nuclear envelope at the onset of anaphase (Asencio et al., 2012; pubmed:22770216). [from MIM:616062; 2016.06.16]
One to one: 1 human to 1 Drosophila.
Ortholog of human ANKLE2 (1 Drosophila to 1 human). Dmel\Ankle2 shares 23% identity and 35% similarity with human ANKLE2.
