HGNC Approved Gene Symbol: NUP88Cytogenetic location: 17p13.2 Genomic coordinates (GRCh38): 17:5,384,832-5,419,661 (from NCBI)▼ Cloning and ExpressionBy copr...
HGNC Approved Gene Symbol: NUP88
Cytogenetic location: 17p13.2 Genomic coordinates (GRCh38): 17:5,384,832-5,419,661 (from NCBI)
▼ Cloning and Expression
By coprecipitation with CAN (114350), Fornerod et al. (1997) identified a novel nuclear pore complex (NPC) component that they called NUP88. Fornerod et al. (1997) derived cDNAs encoding NUP88 from the dBEST database and from screening a human placental cDNA library. By combining sequence information from these sources, they constructed 2 overlapping cDNA contigs that diverged at their 3-prime ends. The cDNAs, measuring 2,359 and 3,489 bp, were colinear until nucleotide 2323, in the 3-prime untranslated region. Northern blot analysis showed a major transcript of approximately 2.5 kb expressed in every tissue studied, but particularly prominent in testis, and a minor transcript of approximately 3.5 kb, which was most abundant in brain. Fornerod et al. (1997) found that the NUP88 cDNA predicted a protein of 741 amino acids with a molecular mass of 85 kD. The protein migrated at 88 kD and was therefore named NUP88 to distinguish it from NUP85. Fornerod et al. (1997) stated that the C-terminal region of NUP88 has sequences predicted to form a coiled-coil, an interaction domain often found in NPC proteins. Depletion of CAN from the NPC results in concomitant loss of NUP88, indicating that localization of NUP88 to the NPC is dependent on CAN binding (Fornerod et al., 1997).
The NUP88 gene maps to human chromosome 17p13 by fluorescence in situ hybridization (Fornerod et al., 1997).
▼ Molecular Genetics
In affected patients from 2 unrelated families with fetal akinesia deformation sequence-4 (FADS4; 618393), 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.
▼ ALLELIC VARIANTS ( 3 Selected Examples):
.0001 FETAL AKINESIA DEFORMATION SEQUENCE 4
In 2 sibs, conceived of consanguineous Palestinian parents (family A) with fetal akinesia deformation sequence-4 (FADS4; 618393), Bonnin et al. (2018) identified a homozygous c.1300G-T transversion (c.1300G-T, NM_002532.5) in exon 9 of the NUP88 gene, resulting in an asp434-to-tyr (D434Y) substitution at a conserved residue. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the dbSNP, ExAC, or gnomAD databases. DNA was unavailable from 2 prior miscarriages of similarly affected fetuses. Molecular modeling indicated that the D434Y mutation is located in a helix-turn-helix motif between 2 beta-strands and would likely lead to destabilization of the NUP88 protein complex.
.0002 FETAL AKINESIA DEFORMATION SEQUENCE 4
In a male fetus, conceived of unrelated parents of European descent (family B), with fetal akinesia deformation sequence-4 (FADS4; 618393), Bonnin et al. (2018) identified compound heterozygous mutations in the NUP88 gene: a c.1525C-T transition (c.1525C-T, NM_002532.5) in exon 11, resulting in an arg509-to-ter (R509X) substitution, and a 3-bp in-frame deletion in exon 14 (c.1899_1901del; 602552.0003), resulting in the deletion of highly conserved residue glu634 (E634del). The mutations, which were found by exome sequencing, segregated with the disorder in the family. Neither variant was found in the dbSNP, ExAC, or gnomAD databases. Molecular modeling suggested that both mutations would result in impaired NUP88 protein interactions.
.0003 FETAL AKINESIA DEFORMATION SEQUENCE 4
NUP88, 3-BP DEL, NT1899
For discussion of the 3-bp in-frame deletion (c.1899_1901del, NM_002532.5) in the NUP88 gene, resulting in the deletion of highly conserved residue glu634 (E634del), that was found in compound heterozygous state in a patient with fetal akinesia deformation sequence-4 (FADS4; 618393) by Bonnin et al. (2018), see 602552.0002.