Fetal Akinesia Deformation Sequence 4

A number sign (#) is used with this entry because of evidence that fetal akinesia deformation sequence-4 (FADS4) is caused by homozygous or compound heterozygous mutation in the NUP88 gene (602552) on chromosome 17p13.

Description

Fetal akinesia deformation sequence-4 (FADS4) is an autosomal recessive disorder characterized by decreased fetal movements due to impaired neuromuscular function, resulting in significant congenital contractures and death in utero or soon after birth (summary by Bonnin et al., 2018).

For a general phenotypic description and a discussion of genetic heterogeneity of FADS, see 208150.

Clinical Features

Bonnin et al. (2018) reported 4 sibs, conceived of consanguineous Palestinian parents (family A), with lethal arthrogryposis multiplex congenita (AMC). The only live-born infant died at 2 days of age; the other 3 died in utero either through miscarriage or termination of pregnancy due to affected status. A single male fetus from a second family of European descent (family B) with a similar phenotype was also reported. Decreased fetal movements were noted during the pregnancies. The infant and affected fetuses had similar contractures of the fingers, hands, and elbows, as well as kyphosis, rocker-bottom feet, and muscle atrophy. Dysmorphic features included low-set, posteriorly rotated ears, high broad nasal bridge, high-arched palate, microretrognathism, reduced number of rib pairs, short, broad, or hyperextended neck, and undescended testes. Two of the pregnancies were complicated by polyhydramnios, and another fetus had body edema, pleural effusions, and ascites.

Inheritance

The transmission pattern of FADS4 in the families reported by Bonnin et al. (2018) was consistent with autosomal recessive inheritance.

Molecular Genetics

In affected patients from 2 unrelated families with FADS4, Bonnin et al. (2018) identified homozygous or compound heterozygous mutations in the NUP88 gene (602522.0001-602522.0003). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. In vitro functional expression studies in HeLa cells showed that the mutations had distinct effects on the interaction of NUP88 with binding partners within the nuclear core complex, but these changes were not considered significant enough to account for the phenotype. Further studies in HeLa and C2C12 myoblast cells showed that depletion of NUP88 resulted in decreased rapsyn (601592) levels, and muscle biopsy from 1 of the affected fetuses showed decreased and irregular rapsyn distribution compared to controls, which may indicate impaired formation of the neuromuscular junction. Expression of the corresponding mutations in zebrafish failed to rescue the abnormal phenotype of nup88-null zebrafish, suggesting that all 3 human NUP88 variants are functionally inactive. Bonnin et al. (2018) concluded that absence of functional NUP88 causes fetal akinesia at least in part through misregulation of rapsyn expression.

Animal Model

Bonnin et al. (2018) found that the zebrafish ortholog of nup88 was ubiquitously expressed soon after fertilization, with high levels of expression in proliferative frontal regions of the embryo, such as the central nervous system, brain, eye, and anterior trunk. Mutant zebrafish carrying a homozygous nonsense mutation in the nup88 gene had abnormally small heads and eyes, severe abnormalities of the ventral viscerocranium and pharyngeal arches, lack of a protruding mouth, downward curvature of the anterior-posterior axis, abnormal gut, and aplastic swim bladder. The reduced size of head and eyes correlated with an increase in apoptotic cells. Mutant zebrafish also showed impaired locomotor behavior and had decreased survival compared to wildtype. Skeletal muscle fibers from mutant animals showed reduced rapsyn levels, as well as impaired AChR clustering in fast-twitch muscle fiber synapses, likely reflecting impaired formation of the neuromuscular junction.