Meiotic stability and genotype – phenotype correlation of the trinucleotide repeat in X–linked spinal and bulbar muscular atrophy

Ar, La Spada; Db, Roling; Harding, A E; Cl, Warner; Spiegel, Roland; Hausmanowa-Pétrusewicz, I; Wc, Yee; Fischbeck, K. H.

doi:10.1038/ng1292-301

Cited by 344 publications

(160 citation statements)

References 19 publications

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“…However, one of the poorly understood features of expansion is the gender bias that is associated with transmission. Large changes in repeat number are known to be transmitted through the paternal line in HD (1, 2), SCA1 (3), dentatorubral-pallidoluysian atrophy (DRPLA) (4), MachadoJoseph disease (5), and spinal and bulbar muscular atrophy (SBMA) (6) and through the maternal line in Fragile X (7,8). The gender bias transmission has also been documented in transgenic mice (9 -12).…”

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confidence: 99%

CAG Repeat Lengths in X- and Y-bearing Sperm Indicate That Gender Bias during Transmission of Huntington's Disease Gene Is Determined in the Embryo

Kovtun

Welch

Guthrie

et al. 2004

Journal of Biological Chemistry

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The size of the CAG tract at the Huntington's disease (HD) locus upon transmission depends on the gender of the parent. However, the basis for the parent-of-origin effect is unknown. To test whether expansion and contraction in HD are "imprinted" in the germ cells, we isolated the X-and Y-bearing sperm of HD transgenic mice. Here we show that CAG repeat distributions in the X-and Y-bearing spermatozoa of founding fathers do not differ. These data show that gender-dependent changes in CAG repeat length arise in the embryo.The mechanism for expansion in HD 1 and other trinucleotide disorders is not known. However, one of the poorly understood features of expansion is the gender bias that is associated with transmission. Large changes in repeat number are known to be transmitted through the paternal line in HD (1, 2), SCA1 (3), dentatorubral-pallidoluysian atrophy (DRPLA) (4), MachadoJoseph disease (5), and spinal and bulbar muscular atrophy (SBMA) (6) and through the maternal line in Fragile X (7, 8). The gender bias transmission has also been documented in transgenic mice (9 -12). Similar to humans, HD transgenic mice transmit expansions predominantly through the male germ line (9,10,12). Moreover, we found that expansion and contraction of CAG repeat size in the hHD transgene depended on the gender of the progeny (9).Expansions are primarily seen in males and contractions dominate in females. The molecular basis for the parent-oforigin effect is unknown. The gender dependence of expansion can be due to differences in CAG repeat distribution in X-and Y-bearing sperm. Alternatively, the change in repeat number, contraction, or expansion can take place after fertilization in early embryogenesis. In order to distinguish between these two mechanisms, the isolation and purification of the X-and Ybearing sperm were required. This, however, was not possible using conventional technology.In present work, we have developed techniques and used advanced technology to separate pure populations of X-and Y-bearing germ cells from HD transgenic mice. We show here that CAG repeat distributions in X-and Y-bearing parental sperm are not different. Repeat expansion occurs equally well within both X and Y chromosomes. This indicates that the gender-dependent processing of CAG repeats must take place post-zygotically. Thus, these data provide evidence for a new kind of imprinting that may be important in the interpretation of genetic data in other systems. EXPERIMENTAL PROCEDURESAnimals-HD transgenic male mice (line B6CBA-TgN R6/1) were originally purchased from The Jackson Laboratory. The colony was maintained at the animal core facility, Mayo Clinic/Foundation. Animals were routinely screened for the presence of HD transgene by PCR (10, 18).Preparation of Single Cell Suspension and Flow Sorting-Mouse epididymis was dissected from the animal, placed in phosphate-buffered saline, and chopped with a razor. Resulting suspension was filtered through cheesecloth. The supernatant was centrifuged at 1500 rpm, and the pellet was resuspended...

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CAG Repeat Lengths in X- and Y-bearing Sperm Indicate That Gender Bias during Transmission of Huntington's Disease Gene Is Determined in the Embryo

Kovtun

Welch

Guthrie

et al. 2004

Journal of Biological Chemistry

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“…In SBMA patients, a normally polymorphic CAG repeat (10 -36 CAGs) expands to 38 -66 CAGs. The number of CAGs is inversely correlated with the age of onset of the disease (2)(3)(4). To date, seven other CAG repeat diseases have been identified, including Huntington's disease (5), dentatorubralpallidoluysian atrophy (6,7), and five spinocerebellar ataxias: 1, 2, 3, 6, and 7) (8 -14).…”

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confidence: 99%

Chaperones Hsp70 and Hsp40 Suppress Aggregate Formation and Apoptosis in Cultured Neuronal Cells Expressing Truncated Androgen Receptor Protein with Expanded Polyglutamine Tract

Kobayashi¹,

Kume²,

Li³

et al. 2000

Journal of Biological Chemistry

302

165

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Spinal and bulbar muscular atrophy (SBMA) is one of a group of human inherited neurodegenerative diseases caused by polyglutamine expansion. We have previously demonstrated that the SBMA gene product, the androgen receptor protein, is toxic and aggregates when truncated. Heat shock proteins function as molecular chaperones, which recognize and renaturate misfolded protein (aggregate). We thus assessed the effect of a variety of chaperones in a cultured neuronal cell model of SBMA. Overexpression of chaperones reduces aggregate formation and suppresses apoptosis in a cultured neuronal cell model of SBMA to differing degrees depending on the chaperones and their combinations. Combination of Hsp70 and Hsp40 was the most effective among the chaperones in reducing aggregate formation and providing cellular protection, reflecting that Hsp70 and Hsp40 act together in chaperoning mutant and disabled proteins. Although Hdj2/Hsdj chaperone has been previously reported to suppress expanded polyglutamine tract-formed aggregate, Hsdj/Hdj2 showed little effect in our system. These findings indicate that chaperones may be one of the key factors in the developing of CAG repeat disease and suggested that increasing expression level or enhancing the function of chaperones will provide an avenue for the treatment of CAG repeat disease.

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“…To prevent misdiagnoses, we simultaneously applied two genotyping methods: a direct analysis for the number of CAG repeats in exon 1 of the AR gene and sex determination by amplification of the SRY gene to diagnose SBMA. SBMA is caused by an expansion of the CAG repeat in exon 1 of the AR gene, and individuals with more than 40 CAG repeats should be diagnosed with SBMA; the average CAG repeat length from patients with SBMA is 47 CAGs [29]. Patients with SBMA have two important clinical features, one is slowly progressive weakness and atrophy in the limb and bulbar muscles and the other one is androgen insensitivity.…”

Section: Discussionmentioning

confidence: 99%

“…Patients with SBMA usually present muscle weakness in their midforties [32]. However, the age of disease onset correlates inversely with the CAG repeat length, i.e., greater CAG repeat lengths correspond to earlier disease onset [29]. Christopher Grunseich et al reported a 29-year-old patient with SBMA who had 68 CAG repeats in the AR gene and who had presented weakness since age 18 [14].…”

Section: Discussionmentioning

confidence: 99%

The clinical application of preimplantation genetic diagnosis for the patient affected by congenital contractural arachnodactyly and spinal and bulbar muscular atrophy

Chen

Diao

et al. 2016

J Assist Reprod Genet

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Purpose To investigate the usefulness of preimplantation genetic diagnosis (PGD) for the patient affected by congenital contractural arachnodactyly (CCA) and spinal and bulbar muscular atrophy (SBMA). Methods Multiple displacement amplification (MDA) was performed for whole genome amplification (WGA) of biopsied trophectoderm (TE) cells. Direct mutation detection by sequencing and next-generation sequencing (NGS)-based single nucleotide polymorphism (SNP) haplotyping were used for CCA diagnosis. Direct sequencing of the PCR products and sex determination by amplification of sexdetermining region Y (SRY) gene were used for SBMA diagnosis. After PGD, the unaffected blastocyst (B4) was transferred in the following frozen embryo transfer (FET). Results In this PGD cycle, sixteen MII oocytes were inseminated by ICSI with testicular spermatozoa. Four blastocysts (B4, B5, B10, B13) were utilized for TE cell biopsy on day 5 after ICSI. After PGD, B4 was unaffected by CCA and SBMA. B5 was affected by CCA and carried SBMA. B10 was unaffected by CCA and carried SBMA. B13 was affected by CCA and unaffected by SBMA. B4 was the only unaffected blastocyst and transferred into the uterus for the subsequent FET cycle. The accuracy of PGD was confirmed by amniocentesis at 21 weeks of gestation. A healthy boy weighing 2850 g was born by cesarean section at the 38th week of gestation. Conclusions PGD is a valid screening tool for patienst affected of CCA and SBMA to prevent transmission of these genetic diseases from parents to children.Keywords Congenital contractural arachnodactyly . Spinal and bulbar muscular atrophy . PGD . Frozen embryo transfer Capsule A description of a PGD cycle for the diagnosis of CCA and SBMA, resulting in the birth of a healthy boy.Linjun Chen and Zhenyu Diao contributed equally to this work.

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Meiotic stability and genotype – phenotype correlation of the trinucleotide repeat in X–linked spinal and bulbar muscular atrophy

Cited by 344 publications

References 19 publications

CAG Repeat Lengths in X- and Y-bearing Sperm Indicate That Gender Bias during Transmission of Huntington's Disease Gene Is Determined in the Embryo

CAG Repeat Lengths in X- and Y-bearing Sperm Indicate That Gender Bias during Transmission of Huntington's Disease Gene Is Determined in the Embryo

Chaperones Hsp70 and Hsp40 Suppress Aggregate Formation and Apoptosis in Cultured Neuronal Cells Expressing Truncated Androgen Receptor Protein with Expanded Polyglutamine Tract

The clinical application of preimplantation genetic diagnosis for the patient affected by congenital contractural arachnodactyly and spinal and bulbar muscular atrophy

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