Meckel Syndrome 12

A number sign (#) is used with this entry because of evidence that Meckel syndrome-12 (MKS12) is caused by compound heterozygous mutation in the KIF14 gene (611279) on chromosome 1q31. One such family has been reported.

For a general phenotypic description and a discussion of genetic heterogeneity of Meckel syndrome, see MKS1 (249000).

Clinical Features

Filges et al. (2014) reported 2 sisters, conceived by unrelated Caucasian parents, with a lethal fetal congenital anomaly syndrome. Prenatal ultrasound showed oligohydramnios, intrauterine growth retardation with microcephaly, complex brain malformations, and renal anomalies. The pregnancies were terminated, and autopsy confirmed the ultrasound findings. Features included cerebral and cerebellar hypoplasia, renal agenesis or hypoplasia, ureteral hypoplasia, uterine hypoplasia, and flexion arthrogryposis. One fetus also had agenesis of the corpus callosum, arhinencephaly, and vaginal atresia, whereas the other had agenesis of the occipital lobes. Secondary facial features resulting from oligohydramnios were also present.

Inheritance

The transmission pattern of MKS12 in the family reported by Filges et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sib fetuses with MKS12, Filges et al. (2014) identified compound heterozygous truncating mutations in the KIF14 gene (611279.0001 and 611279.0002). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Both mutations were predicted to result in nonsense-mediated mRNA decay, consistent with a complete loss of function. Additional functional studies were not performed, but reexamination of histologic brain and kidney sections from 1 of the affected fetuses showed a high number of binucleated cells compared to controls, suggesting disruption of cell cycle progression and failure of cytokinesis.

Animal Model

Fujikura et al. (2013) described a spontaneous mouse mutant, 'laggard' (lag), which was characterized by growth retardation, microcephaly, flat head, and motor impairment. Positional cloning studies showed that the lag mouse resulted from a homozygous splice site mutation in the Kif14 gene, which caused loss of the wildtype protein. Homozygous mutant mice showed progressive severe ataxia, tremors, and muscle weakness, and died within 3 weeks of birth. Neuropathologic examination showed that the brains of mutant mice were small compared to wildtype, with dysgenesis of the cerebral and cerebellar cortices and the hippocampus, and severe hypomyelination of the brain and spinal cord. Gene expression studies showed a dramatic reduction in the expression of genes involved in myelination and maturation of oligodendrocytes. Mutant mice also displayed a dramatic increase in neuronal apoptosis.