Mutations In Cystatin Research Articles

Isolation and characterization of autoantibodies against human cystatin C.

Hereditary cystatin C amyloid angiopathy (HCCAA) is a severe neurodegenerative disorder related to the point mutation in cystatin C gene resulting in human cystatin C (hCC) L68Q variant. One of the potential immunotherapeutic approaches to HCCAA treatment is based on naturally occurring antibodies against cystatin C. A recent growing interest in autoantibodies, especially in the context of neurodegenerative diseases, emerges from their potential use as valuable diagnostic markers and for controlling protein aggregation. In this work, we present characteristics of natural anti-hCC antibodies isolated from the IgG fraction of human serum by affinity chromatography. The electrophoresis (1-D and 2-D) results demonstrated that the isolated NAbs are a polyclonal mixture, but their electrophoretic properties did not allow to classify the new autoantibodies to any particular type of IgG. The Fc-glycan status of the studied autoantibodies was assessed using mass spectrometry analysis. For the isolated NAbs, the epitopic fragments in hCC sequence were identified by MS-assisted proteolytic excision of the immune complex and compared with the ones predicted theoretically. The knowledge of hCC fragments binding to NAbs and other ligands may contribute to the search for new diagnostic methods for amyloidosis of different types and the search for their treatment.

SCARB2 mutations in progressive myoclonus epilepsy (PME) without renal failure

Mutations in SCARB2 were recently described as causing action myoclonus renal failure syndrome (AMRF). We hypothesized that mutations in SCARB2 might account for unsolved cases of progressive myoclonus epilepsy (PME) without renal impairment, especially those resembling Unverricht-Lundborg disease (ULD). Additionally, we searched for mutations in the PRICKLE1 gene, newly recognized as a cause of PME mimicking ULD. We reviewed cases of PME referred for diagnosis over two decades in which a molecular diagnosis had not been reached. Patients were classified according to age of onset, clinical pattern, and associated neurological signs into "ULD-like" and "not ULD-like." After exclusion of mutations in cystatin B (CSTB), DNA was examined for sequence variation in SCARB2 and PRICKLE1. Of 71 cases evaluated, 41 were "ULD-like" and five had SCARB2 mutations. None of 30 "not ULD-like" cases were positive. The five patients with SCARB2 mutations had onset between 14 and 26 years of age, with no evidence of renal failure during 5.5 to 15 years of follow-up; four were followed until death. One living patient had slight proteinuria. A subset of 25 cases were sequenced for PRICKLE1 and no mutations were found. Mutations in SCARB2 are an important cause of hitherto unsolved cases of PME resembling ULD at onset. SCARB2 should be evaluated even in the absence of renal involvement. Onset is in teenage or young adult life. Molecular diagnosis is important for counseling the patient and family, particularly as the prognosis is worse than classical ULD.

Hereditary cystatin C amyloid angiopathy: genetic, clinical, and pathological aspects.

Hereditary cystatin C amyloid angiopathy (HCCAA) is a rare, fatal amyloid disease in young people in Iceland caused by a mutation in cystatin C, which is an inhibitor of several cysteine proteinases, such as cathepsins S, B, and K. The same mutation in cystatin C, L68Q, has been found in all patients examined so far pointing to a common founder. Most of the families can be traced to a region in the northwest of Iceland, around Breidafjordur bay. Mutated cystatin C forms amyloid, predominantly in brain arteries and arterioles, but also to a lesser degree in tissues outside the central nervous system such as skin, lymph nodes, testis, spleen, submandibular salivary glands, and adrenal cortex. The amyloid deposition in the vessel walls causes thickening of the walls leading to occlusion or rupture and resulting in brain hemorrhage. Although the amyloid can be detected outside the brain, the clinical manifestation is restricted to the brain, and usually consists of repeated hemorrhages leading to paralysis. Sometimes the initial signs of hemorrhage are dementia and personality changes.

The epilepsy, the protease inhibitor and the dodecamer: progressive myoclonus epilepsy, cystatin b and a 12-mer repeat expansion

Progressive myoclonus epilepsy 1 (EPM1) or Unverricht-Lundborg disease is a human autosomal recessive neurodegenerative disorder caused by mutations in cystatin B (CSTB). The CSTB gene maps to human chromosome 21 and encodes an inhibitor of lysosomal cysteine proteases. Five point mutations have been found, two of which are seen in numerous unrelated patients. However, the main CSTB mutation in EPM1, even among patients of different ethnic origins, is an expansion of a dodecamer repeat (CCCCGCCCCGCG) in the 5′ flanking area of CSTB. Most normal alleles contain either two or three repeats, while rarer normal alleles that are highly unstable contain between 12 and 17 repeats. Mutant expanded alleles have been reported to contain between 30 and 80 copies and are also highly unstable, particularly via parental transmission. There is no apparent correlation between mutant repeat length and disease phenotype. While the repeat expansion is outside the CSTB transcriptional unit, it results in a marked decrease in CSTB expression, at least in certain cell types in vitro. Cstb homozygous knockout mice show some parallels to the phenotype of human EPM1 including myoclonic seizures, development of ataxia and neuropathological changes associated with cell loss via apoptosis. Loss of CSTB function due to mutations is consistent with the observed neurodegenerative pathology and phenotype, but the functional link to the epileptic phenotype of EPM1 remains largely unknown.

The cystatin C polymorphism is not associated with early onset Alzheimer's disease.

There is growing evidence that vascular factors are involved in AD.1 In light of these findings, a polymorphism in the cystatin C gene ( CST3 ) that was recently found to be associated with late onset AD is a promising candidate gene.2 Cystatin C is an amyloidogenic protein found together with β-amyloid in the arteriolar walls of patients with AD and patients with congophilic amyloid angiopathy (CAA).3 As CAA is also a prominent feature in early onset AD and Down syndrome4 and a mutation in cystatin C leads to CAA at very early age5 we investigated the role of the CST3 polymorphism in early onset AD. Patients were derived from a population-based study of early onset AD in the Netherlands, as described in detail before.6 AD was diagnosed using a protocol in accordance with the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s …

Hereditary Ataxias

Hereditary Ataxias