Candidate Gene for Hyperferritinemia

NCT05659017 | Unknown

• 1 other identifier: HyFerr
• Study Type: observational
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

Ferritin is a ubiquitous protein capable of storing iron in the cell cytosol. Stored iron is released and made available for cellular needs by the degradation of ferritin itself. Small amounts of ferritin are present in the blood and consist of ferritin L, a glycosylated form of L called ferritin G, and trace amounts of ferritin H. It is secreted mainly by macrophages, hepatocytes, and lymphoid cells, but most aspects of its secretion remain not fully elucidated. Serum ferritin has broad clinical utility primarily as an indicator of iron stores, so low values of serum ferritin are indicative of a deficient state and high values of iron overload. However, the causes of increased serum ferritin are numerous, in many cases serum ferritin is increased disproportionately to iron stores such as in acute and chronic liver disease, infectious and inflammatory states, metabolic disorders, and high alcohol intake that are frequently observed in the clinical setting. Therefore, the diagnosis of hyperferritinemia requires a careful strategy including personal and family history, biochemical, instrumental, and targeted genetic testing. In fact, there are rare forms of genetically determined hyperferritinemia not associated with iron overload, such as hereditary cataract hyperferritinemia syndrome (HHCS) due to mutations in the Iron responsive Element (IRE) located in the 5' untranslated region of the FTL gene. More recently, a second dominant form of genetic hyperferritinemia without iron overload or cataract (benign hyperferritinemia) has been identified. Preliminary results obtained so far have made it possible, through WES analysis, to identify the involvement of the STAB1 gene, which was found to be mutated in the studied subjects in whom reduced serum ferritin glycosylation and reduced plasma concentration of the protein itself were observed. It is therefore deemed necessary to proceed with the assay of glycosylated ferritin and the protein encoded by the gene to assess its sensitivity and specificity as a predictive test before performing the genetic analysis of STAB1. To achieve this goal, patients with undefined hyperferritinemia afferent to the SSD Rare Diseases of the IRCCS San Gerardo Foundation in whom to perform glycosylated ferritin and STAB1 protein assay in parallel with STAB1 sequencing will be evaluated. Similar investigations will be performed in a control group consisting of cases of hyperferritinemia due to genetically determined iron overload.

Conditions

Hyperferritinemia

Outcome Measures

Primary Outcomes (1)

• Candidate gene sequencing

  For the purpose 100 patients are sufficient to calculate both the allelic and genotypic frequency of mutations in the candidate gene.

  1 year

Secondary Outcomes (1)

• DIAGNOSIS ROUTINE

  1 year

Interventions

Genetic analysis GENETIC

The DNA will then be analyzed with a custom panel designed ad hoc to study the candidate gene by Next Generation Sequencing according to the protocols of the supplier of the kit.

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Hyperferritinemia patients followed at the Rare Diseases Center in San Gerardo Hospital

You may qualify if:

• Among patients referred to the Center for Rare Diseases of Monza will be enrolled only subjects with:
• ferritin \> 1000 g / L in men and \> 500 g / L,
• transferrin saturation \<45%
• absence of hepatic iron overload, evaluated by liver biopsy or MRI, as indicated in the attached flow chart.

You may not qualify if:

• Patients with hyperferritinemia attributable to:
• genetically determined causes \[mutations in the HFE gene (homozygosity or heterozygosity for p.Cys282Tyr, homozygosity for p.His63Asp or compound heterozygosity for variants of p.Cys282Tyr and p. His63Asp), ferroportin and L-Ferritin gene mutations\];
• presence of more than one component of metabolic syndrome (according to NCEP-ATPIII criteria: triglycerides \>150 mg/dL, blood glucose \>100 mg/dL, HDL \<40 mg/dL in men and \<50 mg/dL in women, waist circumference \>102 cm in men and \>88 cm in women; blood pressure ≥130/≥85 mm/Hg);
• alcohol intake \>5 g/day chronic hepatitis,
• history of blood transfusion or parenteral iron treatment,
• late skin porphyria,
• hyperthyroidism,
• presence of cataracts or family history of early-onset cataracts
• acute or chronic inflammatory disorders.

Sponsors & Collaborators

• University of Milano Bicocca: lead

Study Sites (1)

Centre for Rare Disease - Disorders of Iron Metabolism, ASST-Monza, San Gerardo Hospital, European Reference Network - EuroBloodNet

Monza, MB, 20900, Italy

RECRUITING

Related Publications (23)

• Arosio P, Levi S. Cytosolic and mitochondrial ferritins in the regulation of cellular iron homeostasis and oxidative damage. Biochim Biophys Acta. 2010 Aug;1800(8):783-92. doi: 10.1016/j.bbagen.2010.02.005. Epub 2010 Feb 20.

  PMID: 20176086 RESULT

• Torti FM, Torti SV. Regulation of ferritin genes and protein. Blood. 2002 May 15;99(10):3505-16. doi: 10.1182/blood.v99.10.3505. No abstract available.

  PMID: 11986201 RESULT

• Finazzi D, Arosio P. Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration. Arch Toxicol. 2014 Oct;88(10):1787-802. doi: 10.1007/s00204-014-1329-0. Epub 2014 Aug 15.

  PMID: 25119494 RESULT

• Wang J, Pantopoulos K. Regulation of cellular iron metabolism. Biochem J. 2011 Mar 15;434(3):365-81. doi: 10.1042/BJ20101825.

  PMID: 21348856 RESULT

• Cragg SJ, Wagstaff M, Worwood M. Sialic acid and the microheterogeneity of human serum ferritin. Clin Sci (Lond). 1980 Mar;58(3):259-62. doi: 10.1042/cs0580259.

  PMID: 7363568 RESULT

• Santambrogio P, Cozzi A, Levi S, Arosio P. Human serum ferritin G-peptide is recognized by anti-L ferritin subunit antibodies and concanavalin-A. Br J Haematol. 1987 Feb;65(2):235-7. doi: 10.1111/j.1365-2141.1987.tb02271.x.

  PMID: 3828232 RESULT

• Cohen LA, Gutierrez L, Weiss A, Leichtmann-Bardoogo Y, Zhang DL, Crooks DR, Sougrat R, Morgenstern A, Galy B, Hentze MW, Lazaro FJ, Rouault TA, Meyron-Holtz EG. Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway. Blood. 2010 Sep 2;116(9):1574-84. doi: 10.1182/blood-2009-11-253815. Epub 2010 May 14.

  PMID: 20472835 RESULT

• Mack U, Cooksley WG, Ferris RA, Powell LW, Halliday JW. Regulation of plasma ferritin by the isolated perfused rat liver. Br J Haematol. 1981 Mar;47(3):403-12. doi: 10.1111/j.1365-2141.1981.tb02808.x.

  PMID: 7459278 RESULT

• Tran TN, Eubanks SK, Schaffer KJ, Zhou CY, Linder MC. Secretion of ferritin by rat hepatoma cells and its regulation by inflammatory cytokines and iron. Blood. 1997 Dec 15;90(12):4979-86.

  PMID: 9389717 RESULT

• Dorner MH, Silverstone A, Nishiya K, de Sostoa A, Munn G, de Sousa M. Ferritin synthesis by human T lymphocytes. Science. 1980 Aug 29;209(4460):1019-21. doi: 10.1126/science.6967622.

  PMID: 6967622 RESULT

• Byg KE, Milman N, Hansen S, Agger AO. Serum Ferritin is a Reliable, Non-invasive Test for Iron Status in Pregnancy: Comparison of Ferritin with Other Iron Status Markers in a Longitudinal Study on Healthy Pregnant Women; Erythropoiesis. Hematology. 2000;5(4):319-325. doi: 10.1080/10245332.2000.11746526.

  PMID: 11399631 RESULT

• Harrison PM, Arosio P. The ferritins: molecular properties, iron storage function and cellular regulation. Biochim Biophys Acta. 1996 Jul 31;1275(3):161-203. doi: 10.1016/0005-2728(96)00022-9.

  PMID: 8695634 RESULT

• Jacobs A, Worwood M. Ferritin in serum. Clinical and biochemical implications. N Engl J Med. 1975 May 1;292(18):951-6. doi: 10.1056/NEJM197505012921805. No abstract available.

  PMID: 1090831 RESULT

• Chen TT, Li L, Chung DH, Allen CD, Torti SV, Torti FM, Cyster JG, Chen CY, Brodsky FM, Niemi EC, Nakamura MC, Seaman WE, Daws MR. TIM-2 is expressed on B cells and in liver and kidney and is a receptor for H-ferritin endocytosis. J Exp Med. 2005 Oct 3;202(7):955-65. doi: 10.1084/jem.20042433.

  PMID: 16203866 RESULT

• Li JY, Paragas N, Ned RM, Qiu A, Viltard M, Leete T, Drexler IR, Chen X, Sanna-Cherchi S, Mohammed F, Williams D, Lin CS, Schmidt-Ott KM, Andrews NC, Barasch J. Scara5 is a ferritin receptor mediating non-transferrin iron delivery. Dev Cell. 2009 Jan;16(1):35-46. doi: 10.1016/j.devcel.2008.12.002.

  PMID: 19154717 RESULT

• Ravasi G, Pelucchi S, Mariani R, Casati M, Greni F, Arosio C, Pelloni I, Majore S, Santambrogio P, Levi S, Piperno A. Unexplained isolated hyperferritinemia without iron overload. Am J Hematol. 2017 Apr;92(4):338-343. doi: 10.1002/ajh.24641. Epub 2017 Feb 7.

  PMID: 28052375 RESULT

• Aguilar-Martinez P, Schved JF, Brissot P. The evaluation of hyperferritinemia: an updated strategy based on advances in detecting genetic abnormalities. Am J Gastroenterol. 2005 May;100(5):1185-94. doi: 10.1111/j.1572-0241.2005.40998.x.

  PMID: 15842597 RESULT

• Camaschella C, Poggiali E. Towards explaining "unexplained hyperferritinemia". Haematologica. 2009 Mar;94(3):307-9. doi: 10.3324/haematol.2008.005405.

  PMID: 19252171 RESULT

• Kannengiesser C, Jouanolle AM, Hetet G, Mosser A, Muzeau F, Henry D, Bardou-Jacquet E, Mornet M, Brissot P, Deugnier Y, Grandchamp B, Beaumont C. A new missense mutation in the L ferritin coding sequence associated with elevated levels of glycosylated ferritin in serum and absence of iron overload. Haematologica. 2009 Mar;94(3):335-9. doi: 10.3324/haematol.2008.000125. Epub 2009 Jan 27.

  PMID: 19176363 RESULT

• Thurlow V, Vadher B, Bomford A, DeLord C, Kannengiesser C, Beaumont C, Grandchamp B. Two novel mutations in the L ferritin coding sequence associated with benign hyperferritinaemia unmasked by glycosylated ferritin assay. Ann Clin Biochem. 2012 May;49(Pt 3):302-5. doi: 10.1258/acb.2011.011229. Epub 2012 Apr 25.

  PMID: 22535864 RESULT

• Piperno A. Molecular diagnosis of hemochromatosis. Expert Opin Med Diagn. 2013 Mar;7(2):161-77. doi: 10.1517/17530059.2013.763794. Epub 2013 Jan 23.

  PMID: 23530886 RESULT

• Riva A, Trombini P, Mariani R, Salvioni A, Coletti S, Bonfadini S, Paolini V, Pozzi M, Facchetti R, Bovo G, Piperno A. Revaluation of clinical and histological criteria for diagnosis of dysmetabolic iron overload syndrome. World J Gastroenterol. 2008 Aug 14;14(30):4745-52. doi: 10.3748/wjg.14.4745.

  PMID: 18720534 RESULT

• National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002 Dec 17;106(25):3143-421. No abstract available.

  PMID: 12485966 RESULT

Biospecimen

Retention: SAMPLES WITH DNA

EDTA vacuette

MeSH Terms

Conditions

Hyperferritinemia

Interventions

Genetic Testing

Condition Hierarchy (Ancestors)

Iron Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Genetic Techniques; Genetic Services; Health Services; Health Care Facilities Workforce and Services; Diagnostic Services; Preventive Health Services

Central Study Contacts

Raffaella Mariani, Dr.ssa

CONTACT

+390392339555; r.mariani@asst-monza.it

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 12, 2022
• First Posted: December 21, 2022
• Study Start: June 6, 2022
• Primary Completion: January 3, 2024
• Study Completion: September 30, 2024
• Last Updated: January 5, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)