Early onset Paget's disease of bone caused by a novel mutation (78dup27) of the TNFRSF11A gene in a Chinese family

Abstract

Aim: A previous study showed that individuals of Japanese descent affected by early onset familial Paget's disease of bone (PDB) carried a 27-bp duplication at position 75 (75dup27) in the TNFRSF11A gene encoding RANK. Here we report the identification of a novel mutation (78dup27) in exon 1 of TNFRSF11A in a Chinese family with early onset PDB. Methods: We conducted clinical and genetic studies in a non-consanguineous Chinese family with early onset PDB. The entire coding region of TNFRSF11A was amplified and directly sequenced directly. Results: A novel 27-bp duplication in exon 1 (78dup27) in TNFRSF11A was found in four affected individuals and one asymptomatic individual. Although this duplication was the same length as the previously identified mutation (27 bp, from bases 78 to 104), in our patients the nine duplicated amino acids in the RANK signal peptide were LLLLCALLA. The phenotypes of affected individuals in this family overlapped with both early onset PDB and classic PDB, but several distinguishing features were found in our patients. The key difference between our familial PDB and the Japanese early onset PDB was the age of onset, which in most of our patients was during their late 20s (except for the propositus' niece). Another notable difference was that the propositus' son (24 years old), who carried the 78dup27 mutation, had no clinical symptoms or bone abnormalities, except for increased serum ALP, OC and CTX. Conclusion: Our findings may provide a better understanding of the clinical features of early onset PDB and support the notion of a hot spot for mutations in exon 1 of the TNFRSF11A gene.

Juvenile Paget's disease with heterozygous duplication within TNFRSF11A encoding RANK

“…(30) There is also expansion of tubular bones in the hands, and striking sclerosis and widening of the maxilla and mandible. (27) Consideration of PDB2 as a distinct entity gained support in 2009 when Ke et al (35) reported a Chinese kindred with clinical features like Japanese PDB2, (27) but manifesting somewhat later in life, also with a 27-bp but novel tandem duplication (78dup27) in TNFRSF11A that would insert a unique nonapeptide into the signal sequence of RANK.…”

New knowledge on critical osteoclast formation and activation pathways from study of rare genetic diseases of osteoclasts: focus on the RANK/RANKL axis

“…Heterozygous insertion duplication mutations located within the signal peptide region of the RANK gene have been identified as the cause of these diseases. FEO is associated with an 18-base pair (84dup18) tandem duplication leading to an additional six amino acids in the RANK protein, ePDB with an insertion of 27 bp (75dup27 or 78dup27), leading to an additional nine amino acids and ESH with a 15 bp duplication (84dup15), adding five amino acids to RANK [48][49][50][51].…”

Paget's disease of bone—genetic and environmental factors

“…Three rare familial and autosomal dominant skeletal dis orders have been described: familial expansile osteo lysis (FEO), 34,35 expansile skeletal hyperphosphatasia 36 and early onset Paget's disease, 37,38 which exhibit some charac teristics of classic Paget's disease. Each of these disorders develops as a consequence of different insertion mutations in the TNFRSF11A gene, which result in increased osteo clast activity.…”

“…36 Early onset Paget's disease has been described in one Japanese kindred 37 and in one Chinese kindred. 38 In the Japanese kindred, a 27 bp duplication was identified in exon 1 (75dup27) and in the Chinese kindred the 27 bp duplication in exon 1 extended from base 78 (78dup27). Affected individuals in the Japanese kindred experienced hearing impairment, tooth loss, skeletal enlargement and deformity in the second or third decade of life.…”