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A Locus for Familial Skewed X Chromosome Inactivation Maps to Chromosome Xq25 in a Family with a Female Manifesting Lowe Syndrome

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A Locus for Familial Skewed X Chromosome Inactivation Maps to Chromosome Xq25 in a Family with a Female Manifesting Lowe Syndrome J Hum Genet (2006) 51:1030–1036 DOI 10.1007/s10038-006-0049-6 SHORT COMMUNICATION A locus for familial skewed X chromosome inactivation maps to chromosome Xq25 in a family with a female manifesting Lowe syndrome Milena Cau Æ Maria Addis Æ Rita Congiu Æ Cristiana Meloni Æ Antonio Cao Æ Simona Santaniello Æ Mario Loi Æ Francesco Emma Æ Orsetta Zuffardi Æ Roberto Ciccone Æ Gabriella Sole Æ Maria Antonietta Melis Received: 15 June 2006 / Accepted: 3 August 2006 / Published online: 6 September 2006 Ó The Japan Society of Human Genetics and Springer 2006 Abstract In mammals, X-linked gene products can be generations. The OCRL1 ‘‘de novo’’ mutation resides dosage compensated between males and females by in the active paternally inherited X chromosome. X inactivation of one of the two X chromosomes in the chromosome haplotype analysis suggests the presence developing female embryos. X inactivation choice is of a locus for the familial skewed X inactivation in usually random in embryo mammals, but several chromosome Xq25 most likely controlling X chromo- mechanisms can influence the choice determining some choice in X inactivation or cell proliferation. The skewed X inactivation. As a consequence, females description of this case adds Lowe syndrome to the list heterozygous for X-linked recessive disease can mani- of X-linked disorders which may manifest the full fest the full phenotype. Herein, we report a family with phenotype in females because of the skewed X inacti- extremely skewed X inactivation that produced the full vation. phenotype of Lowe syndrome, a recessive X-linked disease, in a female. The X chromosome inactivation Keywords Lowe syndrome Æ Skewed X inactivation Æ studies detected an extremely skewed inactivation X chromosome inactivation Æ Family study pattern with a ratio of 100:0 in the propositus as well as in five out of seven unaffected female relatives in four Introduction M. Cau Æ M. Addis Æ R. Congiu Æ C. Meloni Æ S. Santaniello Æ M. A. Melis (&) In mammals, X-linked gene products can be dosage Dipartimento di Scienze Biomediche e Biotecnologie, compensated between males and females by inactiva- Universita` di Cagliari, via Jenner s/n, 09134 Cagliari, Italy tion of one of the two X chromosomes in the devel- e-mail: [email protected] oping female embryos. The early events in X A. Cao Æ G. Sole inactivation are under the control of the X inactivation Istituto di Neurogenetica e Neurofarmacologia, CNR, center or Xic that contains several elements thought to Selargius (CA), Italy have a role in X inactivation. One of these, Xist, en- codes a large untranslated transcript that is required M. Loi Servizio di Neuropsichiatria. Azienda Ospedaliera and sufficient for X inactivation. At the beginning of G. Brotzu, Cagliari, Italy the X inactivation process, one of the X chromosomes is chosen to remain active and Xist expression is sta- F. Emma bilized on the future inactive X and accumulates in cis Department of Nephrology and dialysis, Bambino Gesu` , Children’s Research Hospital, Rome, Italy (Avner and Heard 2001). The Xist RNA expression is associated with different chromatin modifications, O. Zuffardi Æ R. Ciccone including histone deacetylation, methylation, and Genetica Medica Universita` di Pavia, Pavia, Italy DNA methylation that render and maintain the inac- O. Zuffardi tivation state through direct or indirect recruitment of IRCSS Policlinico San Matteo, Pavia, Italy several proteins (Heard 2005). X inactivation choice is 123 J Hum Genet (2006) 51:1030–1036 1031 usually random in embryo mammals, and genetic Materials and methods studies have revealed that the randomness behaves as a complex trait under the control of multiple genes Family (Clerc and Avner 2006). In mice, this choice has been shown to be under the control of X controlling element We have examined 12 subjects belonging to a large Xce, such that X inactivation is skewed toward the X four-generation family in which one female manifested chromosome possessing the weaker Xce allele, and of Lowe syndrome, a rare X-linked recessive disorder Xist gene and its negative regulator, antisense RNA (Fig. 1). DNA was extracted by standard method from Tsix (Gribnau et al. 2005). In humans, there is evidence peripheral blood of all the family members except the that mutations in XIST promoter result in familial subjects I-1 and II-2 whose DNA was obtained from skewing X inactivation. Both mutations, C(-43)A and lymphoblastoid cell lines because at the time of the C(–43)G (Plenge et al. 1997), affect the CTCF binding analysis they were dead. The propositus (III-8), a 22- efficiency and show the possibility that the choice of X year-old girl, is the third child of non-consanguineous chromosome inactivation is due to the stabilization of a marriage. Family history was negative for OCRL or higher order of chromatin conformation based on eye abnormalities. Her mother had three spontaneous CTCF-XIST promoter complex (Clerc and Avner abortions and died at the age of 40 from disseminated 2006). Although there is existence of strong evidence lymphoma. At the time of her birth, her father (II-3) of the involvement of XIC locus in skewed X inacti- was 33 years old. All the family members are healthy. vation, few reports suggest the possibility that different She was born at term and, soon after birth, congenital loci in X chromosome could contain genes implicated cataract and severe hypotonia was noted. At 1 year of in the skewed X inactivation (Naumova et al. 1998). age, the development of the renal Fanconi Syndrome, In this paper, we report a family in which six out of severe psychomotor retardation and the typical so- eight females show a completely skewed X inactivation matic characteristics of Lowe syndrome led to the transmitted as an X-linked dominant trait in four making of the diagnosis. At that time failure to thrive generations, and in one of these females this had led to was evident. Biochemical blood analysis showed low a manifestation of the full typical picture of Lowe serum phosphorus, normal calcium and PTH in the low syndrome The oculocerebrorenal syndrome of Lowe normal range. Urine analysis detected low osmolarity, (OCRL) (MIM:309000) is a multisystemic disorder hypercalciuria, hyperphosphaturia, generalized hy- affecting the eyes, nervous system and kidney due to peraminoaciduria and low molecular weight protein- mutations in OCRL1 gene locus at Xq26.1 (Nussbaum uria. The renal ultrasound examination showed small, et al. 1997). Lowe syndrome is transmitted as an diffusely hyperechogenic kidneys. Cytogenetic analysis X-linked recessive trait with a high rate of new muta- detected a normal female karyotype. tions, which are responsible for about one-third of the cases (Lin et al. 1997; Addis et al. 2004). However, OCRL1 sequencing several females showing the complete typical clinical manifestations of the syndrome have been described DNA was extracted by standard methods. The 23 (Scholten 1960; Svore et al. 1967; Harris et al. 1979; coding exons and their flanking intronic sequences of Sagel et al. 1970; Yamashina 1981; Hodgson et al. 1986; OCRL1 gene were amplified from genomic DNA using Mu¨ ller et al. 1991). There are several causes for the forward and reverse primers designed according to development of the complete syndrome phenotype of nucleotide sequences (Addis et al. 2004). X-linked recessive disorders in females: cytogenetic abnormalities such as reciprocal translocations involv- XIST sequencing ing the X chromosome; the presence of the 45, X karyotype; uniparental disomy; and skewed X inac- The highly conserved minimal promoter of the XIST tivation. After the exclusion of cytogenetic abnormal- gene located in Xq13 was amplified using primers ities and uniparental disomy, extremely skewed previously described (Plenge et al. 1997) and se- X inactivation was ascertained to be the cause of this quenced. phenotype in the female. This extremely skewed X inactivation was also present in five out of seven Determination of X inactivation pattern phenotypically normal females. X chromosome hap- lotype analysis showed that in this family the skewed In order to study the X-chromosome inactivation pat- X inactivation co-segregates with the chromosomal tern, we used the androgen receptor assay on peripheral region Xq25. blood of all available female family members and 123 1032 J Hum Genet (2006) 51:1030–1036 Fig. 1 Pedigree with DXS1060 3 3 1 2 DXS8051 2 3 I haplotypes obtained using 37 DXS987 4 5 DXS1226 4 3 microsatellite markers of X DXS1214DXS1214 2 1 DXS1068DXS1068 1 3 chromosome. Marker order DXS1058 1 1 DXS993 2 1 DXS1003 1 2 was determined from the DXS988 1 2 DXS991 1 1 GeneLoc integrated map. AR 4 5 DXS1275 3 2 DXS8031 1 2 Boxes indicate the DXS453 2 3 DXS8107 3 4 chromosome region shared by DXS8101 1 3 DXS986 2 4 DXS990 2 4 females with skewed X DXS454 2 1 DXS1106 inactivation (black symbols). DXS8021 2 4 DXS1220 2 1 DXS8055 2 1 Patient with Lowe syndrome DXS8081 2 1 DXS8067 2 1 is marked by the arrow. The DXS1001 5 4 DXS8059 3 4 DXS425 DXS8057 4 3 shaded bar indicates the DXS8009 2 1 DXS6854 1 2 interval region suggestive of DXs6855 2 1 DXS294 DXS1047 3 5 DXS1227DXS1227 2 1 linkage with X inactivation DXS8043DXS8043 3 1 DXS8091DXS8091 2 1 trait observed by Naumova DXS1073DXS1073 1 2 et al. (1998) 1122 3 DXS1060 3 3 2 3 II DXS8051 2 2 3 1 DXS987 4 4 2 4 DXS1226 3 3 2 2 DXS1214 1 2 1 2 DXS1068 1 1 1 1 DXS1058 1 1 2 3 DXS993 2 2 4 1 DXS1003 1 1 2 2 DXS988 2 2 1 1 DXS991 1 1 3 2 AR 4 4 2 1 DXS1275 3 3 4 2 DXS8031 1 1 1 1 DXS453 2 2 1 2 DXS8107 3 3
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