CAG repeat length variation in sperm from a patient with Kennedy's disease

X-linked spinal and bulbar muscular atrophy or Kennedy's disease is an adult-onset motor neuronopathy caused by a CAG repeat expansion within the first exon of an androgen receptor gene. We report the case of a 66-year-old man, previously diagnosed with motor neuron disease (MND), who presented acute and reversible left vocal fold (dysphonia) and pharyngeal paresis, followed by a slowly progressive weakness and also bouts of weakness, wasting and fasciculation on tongue, masseter, face, pharyngeal, and some proximal more than distal upper limb muscles, associated to bilateral hand tremor and mild gynecomastia. There were 5 electroneuromyography exams between 1989 and 2003 that revealed chronic reinnervation, some fasciculations (less than clinically observed) and rare fibrillation potentials, and slowly progressive sensory nerve action potentials (SNAP) abnormality, leading to absent/low amplitude potentials. PCR techniques of DNA analysis showed an abnormal number of CAG repeats, found to be 44 (normal 11-34). Our case revealed an acute and asymmetric clinical presentation related to bulbar motoneurons; low amplitude/absent SNAP with mild asymmetry; a sub-clinical or subtle involvement of proximal/distal muscles of both upper and lower limbs; and a probable evolution with bouts of acute dennervation, followed by an efficient reinnervation.

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Approaches to Sequence the HTT CAG Repeat Expansion and Quantify Repeat Length Variation

Journal of Huntington s Disease ◽

10.3233/jhd-200433 ◽

2021 ◽

Vol 10 (1) ◽

pp. 53-74

Author(s):

Marc Ciosi ◽

Sarah A. Cumming ◽

Afroditi Chatzi ◽

Eloise Larson ◽

William Tottey ◽

...

Keyword(s):

Neurodegenerative Disorder ◽

Disease Onset ◽

Somatic Mosaicism ◽

Genotyping By Sequencing ◽

Repeat Length ◽

Cag Repeat ◽

Length Variation ◽

Allele Size ◽

Pcr Products ◽

Alternative Approaches

Background: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of the HTT CAG repeat. Affected individuals inherit ≥36 repeats and longer alleles cause earlier onset, greater disease severity and faster disease progression. The HTT CAG repeat is genetically unstable in the soma in a process that preferentially generates somatic expansions, the proportion of which is associated with disease onset, severity and progression. Somatic mosaicism of the HTT CAG repeat has traditionally been assessed by semi-quantitative PCR-electrophoresis approaches that have limitations (e.g., no information about sequence variants). Genotyping-by-sequencing could allow for some of these limitations to be overcome. Objective: To investigate the utility of PCR sequencing to genotype large (>50 CAGs) HD alleles and to quantify the associated somatic mosaicism. Methods: We have applied MiSeq and PacBio sequencing to PCR products of the HTT CAG repeat in transgenic R6/2 mice carrying ∼55, ∼110, ∼255 and ∼470 CAGs. For each of these alleles, we compared the repeat length distributions generated for different tissues at two ages. Results: We were able to sequence the CAG repeat full length in all samples. However, the repeat length distributions for samples with ∼470 CAGs were biased towards shorter repeat lengths. Conclusion: PCR sequencing can be used to sequence all the HD alleles considered, but this approach cannot be used to estimate modal allele size or quantify somatic expansions for alleles ⪢250 CAGs. We review the limitations of PCR sequencing and alternative approaches that may allow the quantification of somatic contractions and very large somatic expansions.

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CAG repeat length variation in the Androgen Receptor gene is not associated with spermatogenic failure

Fertility and Sterility ◽

10.1016/j.fertnstert.2007.02.001 ◽

2008 ◽

Vol 89 (1) ◽

pp. 253-259 ◽

Cited By ~ 13

Author(s):

Henrike Westerveld ◽

Liesbeth Visser ◽

Michael Tanck ◽

Fulco van der Veen ◽

Sjoerd Repping

Keyword(s):

Androgen Receptor ◽

Receptor Gene ◽

Androgen Receptor Gene ◽

Repeat Length ◽

Cag Repeat ◽

Length Variation ◽

Spermatogenic Failure

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An investigation into CAG repeat length variation and N/C terminal interactions in the T877A mutant androgen receptor found in prostate cancer

The Journal of Steroid Biochemistry and Molecular Biology ◽

10.1016/j.jsbmb.2008.04.009 ◽

2008 ◽

Vol 111 (1-2) ◽

pp. 138-146 ◽

Cited By ~ 6

Author(s):

Jason Southwell ◽

Shafinaz F. Chowdhury ◽

Bruce Gottlieb ◽

Lenore K. Beitel ◽

Rose Lumbroso ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Repeat Length ◽

Cag Repeat ◽

Length Variation

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Identification of Differentially Expressed Genes in Prostatic Epithelium in Relation to Androgen Receptor CAG Repeat Length

The International Journal of Biological Markers ◽

10.1177/172460080602100205 ◽

2006 ◽

Vol 21 (2) ◽

pp. 96-105 ◽

Cited By ~ 4

Author(s):

C.M. Coutinho-Camillo ◽

E.C. Miracca ◽

M.L. Dos Santos ◽

S. Salaorni ◽

A.S. Sarkis ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Differentially Expressed Genes ◽

Repeat Length ◽

Cag Repeat ◽

Differentially Expressed ◽

Cag Repeats ◽

Pcr Analysis ◽

Length Variation ◽

Rt Pcr

The CAG repeat within exon 1 of the androgen receptor (AR) has been associated with the development of prostate cancer. The shorter number of glutamine residues in the protein has been associated with a higher transcriptional activity of the AR and increased relative risk for prostate cancer. In an attempt to identify differentially expressed genes in prostate cancer in relation to AR CAG repeat length variation, in this study we used total mRNA from normal and tumor tissues from 2 prostate cancer patients with AR alleles containing 19 and 26 CAG repeats to perform differential-display RT-PCR analysis. We were able to identify 48 different transcripts that showed homology to several known genes associated with different biological pathways. Among the differentially expressed genes, ATRX and SFRP1 were further validated by quantitative RT-PCR. The transcripts of both ATRX and SFRP1 genes proved to be down-regulated in most of the prostate tumors analyzed by quantitative RT-PCR. Hypermethylation of the promoter region of the SFRP1 gene was found in 17.5% (7/40) of the cases analyzed and was associated with the loss of SFRP1 expression (p=0.014). The differentially expressed genes identified in this study are implicated in several cellular pathways that, when up- or down-regulated, might play a role in the tumorigenic process of the prostate.

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