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Year : 2016  |  Volume : 143  |  Issue : 2  |  Page : 132-134

Understanding complexity of Fanconi anaemia

Department of Hematology & Lab Services, Apollo Hospitals, Bhubaneswar 751 005, Odisha, India

Date of Web Publication14-Apr-2016

Correspondence Address:
Dipika Mohanty
Department of Hematology & Lab Services, Apollo Hospitals, Bhubaneswar 751 005, Odisha
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0971-5916.180196

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How to cite this article:
Mohanty D. Understanding complexity of Fanconi anaemia . Indian J Med Res 2016;143:132-4

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Mohanty D. Understanding complexity of Fanconi anaemia . Indian J Med Res [serial online] 2016 [cited 2020 May 28];143:132-4. Available from:

Fanconi anaemia (FA) is a clinically heterogeneous disorder with incidence of 1 in 350,000 births and is characterized by bone marrow failure (aplastic anaemia), developmental delay, physical abnormalities and increased incidence of solid tumours and leukaemias [1],[2] . It shows either autosomal or X-linked recessive mode of inheritance. The older patients are at increased risk for squamous cell carcinoma of the head and neck and genitourinary tract. Although an exact mechanism for the FA pathway has yet to be elucidated, it seems to function in sensing DNA damage and repair. The role of FA pathway in cell signaling in response to stress stimuli and in apoptosis is well known [2] . So far, 16 genes (FANCA, B, C, DI/BRACA2, FANCD2, E, F, G, I, J, L, M, N/PALPB2, FANCO/RAD51C, FANCP/SLX4 and FANCQ) have been identified that can be mutated in FA [3] . When DNA damage occurs, the eight FA proteins, A,B,C,E, F, G, L and M that form nuclear core complex at upstream of the pathway monoubiquitinate two other FA proteins FANCD2 and FANCI, resulting in targeting of FANCD2 protein in nuclear foci [4] . FANCD2 (Fanconi anaemia complementation group 2) then interacts with BRCAI and other DNA damage response proteins downstream of the FA pathway such as BRCA2, RAD51 and NBA and repairs the damage [5] . Mutation in the genes at upstream of the FA/BRCA pathway disrupts the pathway and results in non-ubiquitinated FANCD2 protein in the Western blot [6] .

The diagnosis of FA can be done by cytogenetic testing for the increased chromosomal breakages or rearrangements in presence of DNA inter-stand cross-linking agents such as diepoxybutane (DEB) or mitomycin C (MMC) in bone marrow or blood cells. However, molecular analysis is still required for characterization of FA patients and demonstrating pathogenic mutations in the FA genes. Various molecular techniques like multiplex ligation-dependent probe amplification (MLPA) for detection of large deletions, for detection of common point mutations and polymorphisms, high resolution melt (HRM) technique with compatible real-time detection machine followed by confirmatory direct sequencing, direct sequencing for amplified gene regions of genomic DNA or cDNA made from RNA can be used for FANC gene molecular changes. More important is to understand the role of different proteins in Fanconi anaemia pathway. Molecular diagnosis of FA is challenging because of genetic heterogeneity associated with the disease.

In this issue, Moghadam and colleagues from Iran [7] have claimed that HRM (high resolution melting curve) analysis is simpler and more cost-effective than the MLPA procedure. But, the drawback in their investigation is that they have not complemented their 27 patients. In total, six sequence alterations in their study were identified which included two stop codons, two frame-shift mutations, one large deletion and one amino acid exchange. Therefore, their data are not sufficient to pin point the precise defect in FA pathway. Elucidation of the intricacies of the FA pathway will ultimately allow more individualized and efficacious treatment of FA patients and may provide insights into other cancer susceptibility disorders. The interesting findings of this study [7] like absence of congenital abnormality of the kidneys in Iranian patients is worth investigating in FA patients at molecular level.

FA proteins are known to play an important role in DNA damage repair. The phenotype-genotype correlation is the ultimate end for individualistic treatment in these cases. It has become clear from the previous research work that FA-D1 patients are at significant and early risk of progression to AML [8],[9] . This is also important from the point of view of stem cell transplant [10] . Among all complementation groups, FAA accounts for the majority of FA patients (60-65%) followed by FAC (10%) and FAG (9%) [11] .

Literature available from Asia Continent suggests FANCA to be most frequently affected gene among Indian origin Fanconi anaemia patients [11],[12] . First reported FA case from India was with novel large intragenic deletion (exons 8-27 del) in the FANCA gene using MLPA [11],[12],[13] . Moreover, some unpublished data from India (personal communication) also support the prevalence of FAA complementation group. However, reports from eastern Asian countries like Korea and Japan suggest different scenario for FANC genes in Fanconi anaemia. Genotyping study has suggested that mutations in FANCA and FANCG are common in Korean FA patients [14] . They also proved existence of four common founder mutations in an East Asian FA population, two FANCA mutations (c.2546delC and c.3720_3724delAAACA) and two FANCG mutation (c.307+1G>C and c.1066C>T), which had previously been commonly observed in a Japanese FA population [15] . The same authors detected four novel deleterious mutations observed in a Japanese FA population, c.2778+1G>C, c.3627-1G>A, c.1589_1591delATA and c.1761-1G>A of FANCG. In Japanese population most commonly affected FANC genes are FANCA and FANCG, as reported earlier [15] .

Hence, molecular screening in Fanconi anaemia should be prioritized as per frequency of mutated FANC genes amongst specific population under study and suitable molecular technique should be employed to find nature of molecular changes. This can help expand our knowledge towards genotype-phenotype relationship in Fanconi anaemia disorder, where heterogeneity makes the cause obscure.

   References Top

Auerbach A, Buchwald M, Joenje H. Fanconi anemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, editors. The metabolic and molecular bases of inherited disease. New York: MacGraw-Hill; 2001. p. 753-68.  Back to cited text no. 1
D'Andrea AD, Grompe M. Molecular biology of Fanconi anemia: implications for diagnosis and therapy. Blood 1997; 90 : 1725-36.  Back to cited text no. 2
Matsushita N, Endo Y, Sato K, Kurumizaka H, Yamashita T, Takata M, et al. Direct inhibition of TNF-á promoter activity by Fanconi anemia protein FANCD2. PLoS One 2011; 6 : e23324.  Back to cited text no. 3
Longerich S, San Filippo J, Liu D, Sung P. FANCI binds branched DNA and is monoubiquitinated by UBE2T-FANCL. J Biol Chem 2009; 284 : 23182-6.  Back to cited text no. 4
Wang X, Andreassen PR, D'Andrea AD. Functional interaction of monoubiquitinated FANCD2 and BRCA2/FANCD1 in chromatin. Mol Cell Biol 2004; 24 : 5850-62.  Back to cited text no. 5
Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn MS, Timmers C, Hejna J, et al. Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Mol Cell 2001; 7 : 249-62.  Back to cited text no. 6
Moghadam AAS, Mahjoubi F, Reisi N, Vosough P. Investigation of FANCA gene in Fanconi anaemia patients in Iran. Indian J Med Res 2016; 143 : 184-96.  Back to cited text no. 7
Alter BP, Rosenberg PS, Brody LC. Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. J Med g0 enet 2007; 44 : 1-9.  Back to cited text no. 8
Bagby GC, Alter BP. Fanconi anemia. Semin Hematol 2006; 43 : 147-56.  Back to cited text no. 9
Green AM, Kupfer GM. Fanconi anemia. Hematol o0 ncol c0 lin North Am 2009; 23 : 193-214.  Back to cited text no. 10
Vundinti BR. Chromosomal instability and molecular mutations in multispectrum disease of Fanconi anemia. Mol Cytogenet 2014; 7 : 147.   Back to cited text no. 11
Solanki A, Mohanty P, Shukla P, Rao A, Ghosh K, Vundinti BR. FANCA gene mutations with 8 novel molecular changes in Indian Fanconi anemia patients. PLoS One 2016; 11 : e0147016.   Back to cited text no. 12
Shukla P, Rao A, Ghosh K, Vundinti BR. Identification of a novel large intragenic deletion in a family with Fanconi anemia: first molecular report from India and review of literature. Gene 2013; 518 : 470-5.  Back to cited text no. 13
Park J, Chung NG, Chae H, Kim M, Lee S, Kim Y, et al. FANCA and FANCG are the major Fanconi anemia genes in the Korean population. Clin Genet 2013; 84 : 271-5.  Back to cited text no. 14
Yamada T, Tachibana A, Shimizu T, Mugishima H, Okubo M, Sasaki MS. Novel mutations of the FANCG gene causing alternative splicing in Japanese Fanconi anemia. J Hum Genet 2000; 45 : 159-66.  Back to cited text no. 15

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[Pubmed] | [DOI]


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