To the Editor:
We read with great interest the case reported by Fukuhara et al. [1] of a 43-year-old female patient with dyskeratosis congenita, pulmonary fibrosis and heterozygous mutation in TINF2 (telomerase repeat binding factor 1-interacting nuclear factor 2). TIN2, the TINF2 gene product, TERT (telomere reverse transcriptase) and TERC (telomerase RNA component) participate in the regulation of telomere elongation, in which mutations have been previously found to be associated with familial pulmonary fibrosis in adults [2]. Indeed mutations of SFTPC, coding for surfactant protein C, were initially described in children before being described in adults as old as 72 years of age who presented with familial pulmonary fibrosis [3].
However, we were surprised that a TINF2 mutation could be evidenced in an adult of that age. As highlighted by Fukuhara et al. [1], patients with the TINF2 mutation present with severe haematological symptoms before 10 years of age [4]. As mentioned by Fukuhara et al. [1], the identified mutation is probably not hypomorphic because it is a frame-shift deletion located in the mutational “hot spot” described previously. Furthermore, the patient presented with very short telomeres. The TINF2 mutation was probably inherited from her father because he had abnormal skin pigmentation and aplastic anaemia [1].
Re-analysis of the gene mutation sequencing could provide new hypotheses for this late disease onset. Indeed, the electrophoregram depicted in figure 1b in the study by Fukuhara et al. [1] probably comes from a PCR product sub-cloned into an expression vector [5], and does not ensure that the deletion is at the heterozygous status usually seen in our patients (fig. 1). The patient may have experienced a somatic reversion leading to a partial loss of the germline mutation in peripheral blood cells (used for sequencing analysis). Indeed, cells would take advantage of a somatic reversion to become normal, particularly in the blood which is a highly regenerating system. This situation could explain the “milder” phenotype in this patient as compared with “classical” patients with TINF2 mutation. Of note, somatic reversion has been previously reported with TERC mutations [6].
To verify this hypothesis, one could sequence the TINF2 gene of the patient with DNA from other tissue, a buccal swab and/or a lung sample, where the mutation would probably appear as “really” heterozygous. In addition, high throughput sequencing (with next-generation sequencing) of TINF2 in DNA from the patient’s blood should provide precise data on the mutation frequency. However, one cannot definitely exclude the fact that TINF2 mutations could lead to far more heterogeneous clinical phenotypes than previously described.
Footnotes
Conflict of interest: None declared.
- Received February 26, 2014.
- Accepted February 27, 2014.
- © ERS 2014