Disease relevance of USP9X

• Dominantly inherited familial amyloidosis, Finnish type (FAF) is caused by the accumulation of a 71-amino acid amyloidogenic fragment of mutant gelsolin (GSN) [1].
• Familial amyloidosis, Finnish type (FAF), is an autosomal dominant form of familial amyloid polyneuropathy [2].
• Gelsolin-related amyloidosis, also called familial amyloidosis, Finnish type (FAF) is an autosomal dominantly inherited disorder characterized by progressive polyneuropathy and corneal lattice dystrophy [3].
• We have recently shown that in a Danish and a Czech family with a clinical syndrome similar to FAF, including corneal lattice dystrophy, cranial neuropathy and skin changes, the disease is caused by another mutation at the same position, namely 654G-T predicting a Try-for-Asp substitution at 187 in secreted gelsolin [4].
• Orthostatic hypotension was found in 9 of 28 FAF patients, but only in 3 of 69 controls [5].

High impact information on USP9X

• We found the same mutation in a Dutch family but a Danish FAF family had a G654T mutation, predicting Asp to Tyr at residue 187 [1].
• We found a mutation (adenine for guanine) at nucleotide 654 of the gelsolin gene in genomic DNA isolated from five FAF patients [2].
• The mutation and consequent amino acid substitution may lead to the development of FAF [2].
• These two loci have been termed DFFRX and DFFRY for Drosophila fat facets related X and Y. The major transcript detected by EST 221 is-8 kb in size and is expressed widely in a range of 16 human adult tissues [6].
• The association between Itch and FAM/USP9X was confirmed in vitro by glutathione S-transferase pulldown and in vivo through coimmunoprecipation [7].

Chemical compound and disease context of USP9X

• The Asp 187-->Asn (D187N) Asp 187-->Tyr (D187Y) gelsolin mutations facilitate two proteolytic cuts in the parent protein generating a 71-residue fragment that forms amyloid fibrils in humans, putatively causing Finnish type familial amyloidosis (FAF) [8].
• A fluid-accumulating factor (FAF in the ligated rabbit ileal loop test) from a strain of non-O1 Vibrio cholerae not producing cholera toxin-like enterotoxin (CTLT) was partially purified by ammonium sulfate precipitation, gel filtration with Sephadex G-100, and DEAE cellulose column chromatography [9].

Biological context of USP9X

• RESULTS: The expression of USP9Y, USP9X and DDX3Y was found in all the specimens tested, whereas DDX3Yt1 expression was diminished or undetectable in several biopsies with impaired spermatogenesis [10].
• These results thus suggest that in addition to vesicular trafficking, DCX may play a role in the regulation of cell adhesion via its interaction with DFFRX in migrating and differentiating neurons [11].
• To study the origin of the gelsolin mutation in these patients we performed haplotype analysis in 10 Finnish and 2 Japanese FAF families [12].
• Familial amyloidosis, Finnish type (FAF), is an autosomal dominant form of amyloidosis which is related to a point mutation in the gelsolin gene localized on chromosome 9 [13].
• BACKGROUND: Familial amyloidosis of the Finnish type (FAF, Finnish hereditary amyloidosis) is caused by a 654G-A mutation in the gelsolin gene on chromosome 9 resulting in the expression of mutant Asn-187 gelsolin which is abnormally proteolytically processed generating amyloidogenic fragments that polymerize into amyloid fibrils [4].

Anatomical context of USP9X

• We also show that DFFRX associates with microtubules at specific subcellular compartments, including those enriched in DCX [11].
• Rabbit polyclonal antibodies raised to the FAF amyloid not only immunostain the amyloid but also LBs in the cortex and substantia nigra of Parkinson's and diffuse LB disease brains [14].
• Our original FAF patient was demented, and neuropathological analysis showed Alzheimer type brain lesions associated with both classical and cortical Lewy bodies [13].
• Local production, especially in the cornea, conjunctiva, sclera, and ciliary muscle, and systemic deposition, particularly in blood vessles and in the sclera, may contribute to amyloid deposits in FAF [15].
• We report autonomic nervous system and cardiac findings in a study of 30 FAF patients (18 females, 12 males aged 27-74 years; mean 53.9 years) [5].

Associations of USP9X with chemical compounds

• Delta FAF to all dosages of Verap correlated positively with basal plasma epinephrine concentration in EH [16].
• Autopsy eyes from three patients with FAF and ten control eyes were studied by Congo red staining and with antibodies to the nonmutated part of gelsolin (GS-2C4), the mutated gelsolin Asn-187 fragment (AGel), and amyloid-P component (AP) [15].
• The guanine-to-adenine transversion was found in all FAF patients tested, but in none of the control subjects [17].
• NE spillover into the forearm circulation was estimated as the product of delta VA-NE and FAF after three clonidine infusions [18].
• For control group, IVM oocytes were fertilized using frozen-thawed camel spermatozoa separated by swim-up method then suspended in Fert-TALP medium supplemented with 6 mg/ml BSA (FAF) + 10 mug/ml heparin [19].

Other interactions of USP9X

• DFFRX is thought to deubiquitinate specific substrates including beta-catenin, preventing their degradation by the proteasome [11].
• Genotype-phenotype correlations suggest that the presence of a single copy of the DFFRX gene, previously postulated as a gene involved in the ovarian failure seen in Turner syndrome, may be compatible with normal ovarian function, and that there may be a gene for Turner-like features located in distal Xp22.3 [20].

Analytical, diagnostic and therapeutic context of USP9X

• Immunohistochemistry showed that antibodies directed against residues 231-242 of secreted gelsolin, representing the carboxy terminus of the sequence forming the amyloid protein (residues 173-243) laid down in the tissues in a fibrillar form in FAF, specifically labelled the amyloid deposited in rectum and skin in the Danish (654G-T) subtype [4].

References