Identification of DKC1 gene mutations in Japanese patients with X-linked dyskeratosis congenita


Hirokazu Kanegane, Department of Pediatrics, Faculty of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan. E-mail:


Dyskeratosis congenita (DC) is a rare inherited multisystem disorder characterized by the triad of abnormal skin pigmentation, nail dystrophy and mucosal leucoplakia. X-linked recessive inheritances are recognized in approximately 40% of the patients. DKC1 has been identified as the gene responsible for X-linked DC, and genetic analyses have been performed in a worldwide study. Here, we performed genetic analysis of five Japanese patients with presumed X-linked DC, and identified four mutations in the DKC1 gene, including two novel missense mutations (Q31K and T357A). Such genetic analysis is useful for the definite diagnosis and genetic counselling of patients.

Dyskeratosis congenita (DC) is an uncommon inherited disorder characterized by the triad of abnormal skin pigmentation, nail dystrophy and mucosal leucoplakia (Dokal, 2000). Approximately 35% of DC cases have the X-linked form (Mendelian Inheritance in Man, no. 305000), whereas 5% of cases have the autosomal dominant form (MIM 127550) and 60% of cases have the autosomal recessive form (MIM 224230) or are uncharacterized (Marrone & Dokal, 2004). Approximately 80% of patients with DC develop pancytopenia, which represents the main cause of mortality. The gene responsible for X-linked DC has been identified as DKC1 (Heiss et al, 1998). The DKC1 gene encodes a dyskerin, which may be involved in ribosomal RNA biosynthesis, ribosomal unit assembly and/or centromere/microtubule binding. Furthermore, dyskerin belongs to a class of small nuclear ribonucleoprotein particles that is a component of telomerase.

Previous genetic analyses of X-linked DC have shown that the majority of mutations are missense mutations (Marrone & Dokal, 2004). In Japan, two families with DKC1 mutations have been identified: one sporadic case had the recurrent A353V mutation (Yoshimoto et al, 2000), while the other family had a novel mutation, L398P (Hiramatsu et al, 2002). In the present study, we performed a nationwide survey to investigate DKC1 mutations in five Japanese patients with presumed X-linked DC.

Patients and methods


A total of five patients with presumed X-linked DC were enrolled in the present study. Male patients, who had at least two symptoms of the triad of abnormal skin pigmentation, nail dystrophy and mucosal leucoplakia, were diagnosed as presumed X-linked DC. All cases had no family history. Two patients had already undergone bone marrow transplantation (BMT), and preserved samples taken before the BMT were used.

DKC1 mutation detection

DKC1 mutation detection was performed as described previously (Knight et al, 1999a).

Results and discussion

Cases 1–4 were described previously (Kanegane et al, 2002). All cases, except case 5, presented with all the triad of skin pigmentation, nail dystrophy and mucosal leucoplakia (Table I). All of the cases, except case 5, showed pancytopenia or bicytopenia. Cases 2 and 3 showed bone marrow failure before the presentation of skin symptoms. Thus, these patients were initially diagnosed as having acquired aplastic anaemia, and underwent BMT. Although case 2 was well after the BMT, case 3 had serious complications including oesophageal and urethral strictures. Epiphora was observed in two of the five patients. Case 5 showed mental retardation and a short stature.

Table I.  Clinical profiles of the patients with presumed X-linked dyskeratosis congenita.
Case no.12345
  1. MDS-RA, myelodysplastic syndrome-refractory anaemia.

  2. The age when the available sample was taken, prior to bone marrow transplantation, is given in parentheses.

Age at diagnosis (years)86997
Age at test (years)1112 (5)10 (9)167
Family historyNoneNoneNoneNoneNone
Onset of symptoms (age, years)
 Skin pigmentation8699None
 Nail dystrophy56192
 Mucosal leucoplakia76192
 Other symptomsLiver dysfunction Epiphora Oesophageal stricture MDS-RA Urethral strictureEpiphora AlopeciaMental retardation Short stature

Genetic analysis revealed that case 1 had a point mutation (91C→A), leading to the missense mutation (Q31K) (Fig 1). Case 3 had a single base change (1069A→G), causing the missense mutation (T357A). Both of these mutations (Q31K and T357A) were novel. Cases 4 and 5 had the same mutation (1058C→T, A353V), which was known to be a recurrent mutation. Case 2 had no mutations of the coding gene.

Figure 1.

Missense mutations in the DKC1 gene in Japanese patients with X-linked DC. In case 1, 91C was substituted with A in exon 3, resulting in Q31K (A). In case 3, 1069A was substituted with G in exon 11, resulting in T357A (B). In cases 4 and 5, 1058C was substituted with T in exon 11, resulting in A353V (C).

Although all the cases were seemingly sporadic, they were suspected as presumed X-linked DC because of their male gender, and subjected to genetic analysis of DKC1. In the present study, four (80%) of five Japanese patients had DKC1 mutations. In a previous large study, DKC1 mutations were detected in 21 (57%) of 37 families with presumed X-linked DC (Knight et al, 1999a). Patients without DKC1 mutations may have the autosomal form of DC.

The mutations identified in this study were all missense mutations, consistent with previous report (Marrone & Dokal, 2004). The A353V mutation was observed in 10 (48%) of 21 families from any ethnic background (Knight et al, 1999a). In Japan, recurrent A353V has been found in three (50%) of six mutations, including this study (Yoshimoto et al, 2000). The novel Q31K and T357A mutations identified here were located in exons 3 and 11, respectively, which are known as highly mutated exons of the gene. Q31 is a mutated codon in another patient with a Q31E mutation (Wong et al, 2004).

Dyskerin has been implicated not only in ribosomal RNA processing but also in telomerase function. The gene responsible for autosomal dominant DC was identified as TERC, which is a component of telomerase (Vulliamy et al, 2001). DC may be caused by telomerase defects, even when it is the X-linked or autosomal dominant form. The DKC1 gene also accounts for Hoyeraal–Hreidarsson syndrome (MIM 600545), which is characterized by aplastic anaemia, immunodeficiency, microcephaly, cerebellar hypoplasia and growth retardation (Knight et al, 1999b). Thus, X-linked DC and Hoyeraal–Hreidarsson syndrome are considered to be allelic diseases. Case 5 had no immunodeficiency, microcephaly or cerebellar hypoplasia, but presented with mental retardation and a short stature. The patient may represent an incomplete form of Hoyeraal–Hreidarsson syndrome.

There is no specific therapy for DC, but BMT has been performed in patients with aplastic anaemia (Langston et al, 1996; Rocha et al, 1998). However, the outcome of this BMT was not satisfactory due to high morbidity and mortality. In the current study, BMT was undertaken in cases 2 and 3, and case 3 had severe complications, which may be linked to the DC phenotype. These patients were not diagnosed as having DC before the BMT. A few DC patients may be misdiagnosed as having acquired aplastic anaemia prior to BMT. A modified conditioning regimen with fewer myeloablative drugs or avoiding radiotherapy would improve the outcome of BMT in DC patients. A patient with subtle signs of DC should be analysed for DKC1 or TERC gene mutations for a definite diagnosis and further genetic counselling.


We thank the families for providing blood samples and the medical and nursing staff involved in the clinical management of the patients. We also thank Ms Chikako Sakai and Mr Hitoshi Moriuchi for their excellent technical assistance and are grateful to Drs Tomoyuki Mizukami and Hiroyuki Nunoi for helpful discussion. This study was supported by a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology, Japan and grants from the Ministry of Health, Labour and Welfare, Japan.