ABSTRACT
OBJECTIVE: In the course of studies of spastic paraplegias in Russian patients to detect AP4-associated forms, estimate their proportion in the total SPG group and analyze clinical and molecular characteristics. MATERIAL AND METHODS: Five families of Russian ethnicity: four with SPG47, one with SPG51 (4 girls and a boy aged 2.5-9 years) were studied. Clinical and genealogical methods, whole-exome sequencing (WES) and verification by familial Sanger sequencing were used. RESULTS: In our total group, including 118 families with 21 different forms, SPG AP4-associated forms accounted for 4.2% owing mainly to SPG47 (3.4%, 5th place in SPG structure; 20% and 2nd place in AE subgroup.) In non-consanguineous, unrelated SPG47 families three patients had identical genotypes: homozygosity for an earlier reported mutation c.1160_1161 delCA (p.Thr387ArgfsTer30) in AP4B1 exon 6; the 4th patient was compound-heterozygous for the same mutation and novel c.1240C>T (p.Gln414Ter) in exon 7. Frequency of c.1160_1161 delCA may be caused by founder effect in Slavic populations though the idea needs additional studies. The SPG51 patient was compound heterozygous for novel AP4E1 mutations c.2604delA (p.Ser868fs) and c.3346A>G (p.Arg1116Gly). Parent's heterozygosity in all cases was confirmed by Sanger sequencing. Phenotypes were typical: early development delay, muscle hypotony transforming into sever spasticity, mental deficiency, microceplaly (in all SPG47 cases), epilepsy (in 3 SPG47 and SPG51 cases), MRI changes, mainly hydrocephalus and/or hypoplasia of corpus callosum (in 3 SPG47 cases) and few extraneural signs. CONCLUSION: AP4-associated SPG should be taken into consideration in patients with early-onset severe nervous diseases mimicking non-genetic organic CNS disorders and massive exome sequencing (WES or other variants) should be performed.
Subject(s)
Spastic Paraplegia, Hereditary , Child , Child, Preschool , Female , Heterozygote , Homozygote , Humans , Male , Mutation , Pedigree , Phenotype , Russia , Spastic Paraplegia, Hereditary/diagnosis , Spastic Paraplegia, Hereditary/geneticsABSTRACT
JAK/STAT is one of the conservative signaling pathways in higher eukaryotes which plays a critical role in different ontogenesis processes. This article gives a review of the pathway structure at the molecular level, mainly in a model organism Drosophila. There are data about relationship of the signaling pathway and transcription machinery of higher eukaryotes.
