Hypomorphic Mutations in the Gene Encoding a Key Fanconi Anemia Protein, FANCD2, Sustain a Significant Group of FA-D2 Patients with Severe Phenotype

Abstract

FANCD2 is an evolutionarily conserved Fanconi anemia (FA) gene that plays a key role in DNA double-strand-type damage responses. Using complementation assays and immunoblotting, a consortium of American and European groups assigned 29 patients with FA from 23 families and 4 additional unrelated patients to complementation group FA-D2. This amounts to 3%-6% of FA-affected patients registered in various data sets. Malformations are frequent in FA-D2 patients, and hematological manifestations appear earlier and progress more rapidly when compared with all other patients combined (FA-non-D2) in the International Fanconi Anemia Registry. FANCD2 is flanked by two pseudogenes. Mutation analysis revealed the expected total of 66 mutated alleles, 34 of which result in aberrant splicing patterns. Many mutations are recurrent and have ethnic associations and shared allelic haplotypes. There were no biallelic null mutations; residual FANCD2 protein of both isotypes was observed in all available patient cell lines. These analyses suggest that, unlike the knockout mouse model, total absence of FANCD2 does not exist in FA-D2 patients, because of constraints on viable combinations of FANCD2 mutations. Although hypomorphic mutations arie involved, clinically, these patients have a relatively severe form of FA.

Fancd2 −/− mice have hematopoietic defects that can be partially corrected by resveratrol

“…2 In humans, FANCD2 could be essential for embryonic survival, considering that all the FANCD2 mutations identified in human patients are hypomorphic. 24 The fact that Fancc Ϫ/Ϫ mice have a normal-sized KSL stem and progenitor pool could imply that nonubiquitinated Fancd2 has indispensable roles in these developmental processes, as some have recently speculated. 2 An important finding of this study is that Fancd2 Ϫ/Ϫ mice have a compromised marrow environment that is less supportive for stem cell population.…”

“…22,23 Interestingly, there is some evidence that patients with FANCD2 mutations have earlier onset and more rapid progression of hematologic manifestations. 24 It is also noteworthy that all the FANCD2 mutations identified in human patients are hypomorphic, whereas Fancd2 Ϫ/Ϫ mice have null mutations. 21,24 We therefore hypothesized that Fancd2 Ϫ/Ϫ mice might have more severe hematopoietic defects.…”

“…24 It is also noteworthy that all the FANCD2 mutations identified in human patients are hypomorphic, whereas Fancd2 Ϫ/Ϫ mice have null mutations. 21,24 We therefore hypothesized that Fancd2 Ϫ/Ϫ mice might have more severe hematopoietic defects. In this study, we characterized hematopoietic properties of Fancd2 Ϫ/Ϫ mice in detail.…”

The Fanconi anemia ID2 complex: Dueling saxes at the crossroads

“…18,19 However, more recently it has been reported that this complementation group accounts for approximately 6% of all FA patients. 20 Patients belonging to the FA-D2 complementation group display the common FA congenital malformations including skin hypo-or hyper-pigmentation, short stature, and microcephaly ( Table 1). [20][21][22] Importantly, these physical abnormalities, along with skeletal irregularities such as radial ray deformities, often allow for early clinical diagnosis.…”

Incidence of liver abnormalities in Fanconi anemia patients

“…Currently, 15 genes related to FA have been identified [2][3][4], and to date, limited phenotype/genotype correlations have been determined with the exception of cancer incidence in Group D1 [5][6][7].…”