This report describes Sandestig-Stefanova syndrome, which shows autosomal recessive inheritance. The human gene implicated in this disease is NUP188, which encodes a nuclear pore scaffolding protein. There is a single, high-ranking ortholog of NUP188 in Drosophila, Nup188. A few alleles have been generated for Nup188, including non-functional truncations and alleles carrying RNAi targeting constructs.
The human gene NUP188 has not been introduced into flies.
Drosophila lacking Nup188 show defects in dendrite tiling of abdominal ventral multidendritic neurons (FBbt:00002516), suggesting impaired neural circuit formation. Wild-type neurons form densely branching arbors along the body wall, but Nup188-knockout neuronal arbors have gaps, particularly between ddaC (FBbt:00002027) and vdaa (FBbt:00002517) neurons. Escaper adults show impaired climbing behavior and bang-sensitivity (seizure induced by mechanical shock).
[updated Jun. 2020 by FlyBase; FBrf0222196]
[SANDESTIG-STEFANOVA SYNDROME; SANDSTEF](https://omim.org/entry/618804)
[NUCLEOPORIN, 188-KD; NUP188](https://omim.org/entry/615587)
Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation. Characteristic dysmorphic features include small palpebral fissures, a wide nasal bridge and nose, micrognathia, and digital anomalies. All affected individuals died as a result of respiratory failure, and five of them died within the first year of life. Nuclear import of proteins was decreased in affected individuals’ fibroblasts, supporting a possible disease mechanism. (Muir et al. 2020, FBrf0245576.)
Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation. Characteristic dysmorphic features include small palpebral fissures, a wide nasal bridge and nose, micrognathia, and digital anomalies. All affected individuals died as a result of respiratory failure, and five of them died within the first year of life. Nuclear import of proteins was decreased in affected individuals' fibroblasts, supporting a possible disease mechanism. (Muir et al. 2020, FBrf0245576.)
Sandestig-Stefanova syndrome (SANDSTEF) is an autosomal recessive developmental syndrome characterized by pre- and postnatal microcephaly, trigonocephaly, congenital cataract, microphthalmia, facial gestalt, camptodactyly, loss of periventricular white matter, thin corpus callosum, delayed myelinization, and poor prognosis (Sandestig et al. 2019, pubmed:32275884). [from MIM:618804, 2020.06.24]
Of the four unrelated families we identified in this study [Muir et al. 2020, FBrf0245576] two were of Ashkenazi Jewish descent. The three affected individuals from these two unrelated Ashkenazi Jewish families presented with the same two pathogenic NUP188 variants, p.Ile302Valfs∗7 and p.Tyr1048∗, each of which was restricted to the Ashkenazi Jewish population in gnomAD. The higher prevalence of these two variants in the Ashkenazi Jewish population was confirmed by additional targeted screening of a large internationally diverse cohort of Ashkenazi (and Sephardi) healthy Jewish individuals (n = 4,815). This genetic disorder, therefore, will most likely be more prevalent in individuals of Ashkenazi Jewish descent than in the other populations and might have implications for future updates to Ashkenazi Jewish carrier screening. (Muir et al. 2020, FBrf0245576.)
By exome sequencing in 6 girls from 4 families with Sandestig-Stefanova syndrome, Muir et al. 2020 (pubmed:32275884) identified homozygosity or compound heterozygosity for mutations in the NUP188 gene. [from MIM:618804, 2020.06.24]
Of the four unrelated families we identified in this study [Muir et al. 2020, FBrf0245576] two were of Ashkenazi Jewish descent. The three affected individuals from these two unrelated Ashkenazi Jewish families presented with the same two pathogenic NUP188 variants, p.Ile302Valfs*7 and p.Tyr1048*, each of which was restricted to the Ashkenazi Jewish population in gnomAD. The higher prevalence of these two variants in the Ashkenazi Jewish population was confirmed by additional targeted screening of a large internationally diverse cohort of Ashkenazi (and Sephardi) healthy Jewish individuals (n = 4,815). This genetic disorder, therefore, will most likely be more prevalent in individuals of Ashkenazi Jewish descent than in the other populations and might have implications for future updates to Ashkenazi Jewish carrier screening. (Muir et al. 2020, FBrf0245576.)
NUP188 (MIM:615587) is a scaffold nucleoporin and a NUP93 (MIM:614351) subcomplex member that forms the inner ring of the nuclear pore complex (NPC). Disruption of NUP188 in yeast has been shown to inhibit both mRNA export and protein trafficking through the NPC. NUP188 has also been implicated in a diverse range of cellular functions outside of its role in nuclear transport; such functions include ciliogenesis, chromatin organization, transcriptional regulation, and chromosome segregation. (Muir et al. 2020 and references therein, FBrf0245576.)
One to one: 1 human gene to 1 Drosophila gene.
Single, high-scoring ortholog of NUP188.
