Skewed X-inactivation in carriers establishes linkage in an X-linked deafness-mental retardation syndrome.
Skewed X-inactivation in carriers establishes linkage in an X-linked deafness-mental retardation syndrome.
复制标题
携带者中偏向的 X 失活在 X 连锁耳聋-智力低下综合征中建立了联系。
DOI：
10.1002/ajmg.a.30308
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Martin,DonnaM
中科院分区：
文献类型：
--
作者：
Probst,FrankJ;Hedera,Peter;Sclafani,AnthonyM;Pomponi,MariaGrazia;Neri,Giovanni;Tyson,Jessica;Douglas,JulieA;Petty,ElizabethM;Martin,DonnaM
We previously reported three related males with congenital sensorineural hearing loss, mental retardation, short stature, congenital umbilical hernia, facial dysmorphisms, abnormal teeth, widely spaced nipples, and abnormal dermatoglyphics [Martin et al., 2000]. The two older males developed progressive pancytopenia in adulthood. The mode of transmission in this family was consistent with X-linked recessive inheritance, with maternally related, affected males and clinically normal obligate carrier females. Analysis of the three affected males revealed an apparent shared haplotype between DXS1003 and DXS1220, a 68 Mb interval spanning Xq1-21, but linkage analysis using all family members was not performed. Chromosome studies demonstrated no X chromosome anomalies. Since the initial report of this family, the oldest affected individual in the pedigree died of end stage renal disease in his late 50s. An autopsy was not performed. Another individual received a cochlear implant with some improvement in hearing ability. There were no births and no other deaths in the family. Skewing of X chromosome inactivation has been reported in carriers for a number of X-linked recessive diseases [Belmont, 1996; Puck and Willard, 1998], and was previously used to map the gene for alpha-thalassemia/mental retardation syndrome (ATRX;[MIM 301040])[Gibbons et al., 1992]. Skewing of X chromosome inactivation is used clinically to determine carrier status in several X-linked conditions [Belmont, 1996], many of which have mental retardation as a cardinal clinical feature. Acquired skewing of X-inactivation in the peripheral blood cells of women tends to occur with age [Busque et al., 1996; Gale et al., 1997], and X-chromosome inactivation skewing in identical twins usually favors the same chromosome [Christensen et al., 2000], suggesting that complex genetic and environmental factors influence mechanisms of X chromosome inactivation. In our family, both late-onset pancytopenia in affected males and presumed X-linked recessive inheritance raised the possibility of skewed X-inactivation in carrier females and suggested that analysis of skewed X-inactivation may be helpful in refining the map location of the causative locus and identifying carrier females. After obtaining written informed consent, approximately 2–30 ml of peripheral blood was obtained from the three affected males, all obligate carrier females, and all potential carrier females in the pedigree. DNA was isolated from these samples with the Blood & Cell Culture DNA Maxi Kit (Qiagen, Catalog Number 13362) and was diluted to 100 ng/ml in TE. In addition, DNA was obtained from the father of one potential carrier female with the QIAamp DNA Mini Kit (Qiagen, Catalog Number 51304) using two buccal swabs as a tissue source. This study was approved by the Institutional Review Board (IRB) of the University of Michigan. X-inactivation studies were performed via the HUMARAPCR assay, using methods as previously described [Allen et al., 1992]. For linkage studies, DNA from each individual (100 ng) was amplified with primers for all of the following X chromosome markers, essentially as described: DXS1003, DXS988, DXS1225, DXS1210, DXS1059, DXS1072, DXS1220 [Gyapay et al., 1994]; DXS8063, DXS8088 [Dib et al., 1996]; and HUMARA [Allen et al., 1992]. Half of each reaction was run out on a 2% agarose, 1% NuSieve, 0.5 Â TBE gel at 100 V, and the products were scored against each other. In addition, the markers DXS1003, DXS1225, and DXS1059 were run out on a 6% polyacrylamide gel at 60–80 W for 2–3 hr to confirm genotypings.
