Obesity in pycnodysostosis due to UPD1: possible effect of an imprinted gene on chromosome 1.

Pycnodysostosis is a rare autosomal recessive bone disorder that results from loss-of-function mutations in the CTSK gene. This gene is located at chromosome band 1q21 and codes for a lysosomal cysteine protease that functions in bone resorption and remodeling [Gelb et al., 1996]. In the last 40 years, an atypical mode of inheritance (uniparental disomy—UPD) has been recognized as a mechanism responsible for certain genetic disorders. Abnormal genomic imprinting has been detected in several syndromes, including Prader–Willi, Angelman (both in chromosome region 15q11–q13), and Wiedemann–Beckwith (11p15). In addition, the presence of two chromosomes derived from a single parent in an affected individual may be responsible for the homozygosity of autosomal recessive disorders [Kotzot and Utermann, 2005]. Not long after the identification of the CTSK gene in pycnodysostosis, a case of paternal UPD of chromosome 1 (UPD1) was described in a patient with typical pycnodysostosis who was homozygous for a missense mutation present only in the father. Polymorphic DNA markers from chromosome 1 demonstrated that the error occurred due to a meiosis II non-disjunction event [Gelb et al., 1998]. As in this particular case of UPD and pycnodysostosis, all other reported patients with UPD1 do not show unexpected phenotypes aside from the specific condition, suggesting that chromosome 1 is not involved in imprinting disorders [Nimmo et al., 2010]. In further molecular analyses of patients presenting with pycnodysostosis and craniosynosotosis described by Bertola et al. [2010], we determined that one out of six individuals showed paternal UPD1 (case 4). The proposita is an 11-year-old girl, the first child of nonconsanguineous parents, with typical pycnodysostosis, including delayed anterior fontanel closure, multiple bone fractures, short stature, obtuse angle of the mandible, bone sclerosis, and acroosteolysis. She was previously described by Bertola et al. [2010] along with five other patients, all of whom presented with craniosynostosis, previously considered a rare finding in this skeletal dysplasia. Contrary to the others, this patient developed obesity at the age of 8. Endocrine and biochemical analyses showed normal levels of insulin/glycemia, IGFI and IGFBP3, a normal GH response to provocative tests, and moderately elevated levels of leptin. Bidirectional sequencing of the CTSK gene showed a novel homozygous missense mutation, p.Cys318Tyr. The father, but not the mother, was heterozygous for this gene alteration. As UPD1 had already been linked to pycnodysostosis, we performed a microsatellite analysis to investigate whether this mechanism could explain the skeletal dysplasia of our patient. It showed homozygosity for all studied loci in the patient (Fig. 1). Polymorphic markers on chromosome 2 detected biparental inheritance of some markers, thus excluding non-maternity. In autosomal recessive disorders, the parents of affected individuals generally are obligate heterozygotes. This situation can be attributed to consanguinity, especially in rare disorders, to high frequency of the mutant gene in certain populations, or to chance alone. Nevertheless, in the last three decades, UPD has emerged as an alternate mechanism responsible for abnormal phenotypes resulting from homozygosity for autosomal recessive loci. However, the overall importance of this mechanism is not clear. Twentythree cases of UPD for chromosome 1 have been reported, mainly in