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Biomedical subjects

L P Ranum

Publications and source records attributed to L P Ranum.

At least 19 recordsLinked to original sources
PubMed2001

Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9.

Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, can be caused by a mutation on either chromosome 19q13 (DM1) or 3q21 (DM2/PROMM). DM1 is caused by a CTG expansion in the 3' untranslated region of the dystrophia myotonica-protein kinase gene (DMPK). Several mechanisms have been invoked to explain how this mutation, which does not alter the protein-coding portion of a gene, causes the specific constellation of clinical features characteristic of DM. We now report that DM2 is caused by a CCTG expansion (mean approximately 5000 repeats) located in intron 1 of the zinc finger protein 9 (ZNF9) gene. Parallels between these mutations indicate that microsatellite expansions in RNA can be pathogenic and cause the multisystemic features of DM1 and DM2.

Alleles↗
PubMed2000

Spinocerebellar ataxia type 8: clinical features in a large family.

OBJECTIVE: To compare the clinical and genetic features of the seven-generation family (MN-A) used to define the spinocerebellar ataxia 8 (SCA8) locus. BACKGROUND: The authors recently described an untranslated CTG expansion that causes a novel form of SCA (SCA8) characterized by reduced penetrance and complex patterns of repeat instability. METHODS: Clinical and molecular features of 82 members of the MN-A family were evaluated by neurologic examination, quantitative dexterity testing, and, in some individuals, MRI and sperm analyses. RESULTS: SCA8 is a slowly progressive, predominantly cerebellar ataxia with marked cerebellar atrophy, affecting gait, swallowing, speech, and limb and eye movements. CTG tracts are longer in affected (mean = 116 CTG repeats) than in unaffected expansion carriers (mean = 90, p < 10-8). Quantitative dexterity testing did not detect even subtle signs of ataxia in unaffected expansion carriers. Surprisingly, all 21 affected MN-A family members inherited an expansion from their mothers. The maternal penetrance bias is consistent with maternal repeat expansions yielding alleles above the pathogenic threshold in the family (>107 CTG) and paternal contractions resulting in shorter alleles. Consistent with the reduced penetrance of paternal transmissions, CTG tracts in all or nearly all sperm (84 to 99) are significantly shorter than in the blood (116) of an affected man. CONCLUSIONS: The biologic relationship between repeat length and ataxia indicates that the CTG repeat is directly involved in SCA8 pathogenesis. Diagnostic testing and genetic counseling are complicated by the reduced penetrance, which often makes the inheritance appear recessive or sporadic, and by interfamilial differences in the length of a stable (CTA)n tract preceding the CTG repeat.

Adult↗
PubMed2000

SCA8 CTG repeat: en masse contractions in sperm and intergenerational sequence changes may play a role in reduced penetrance.

We recently described an untranslated CTG expansion that causes a previously undescribed form of spinocerebellar ataxia (SCA8). The SCA8 CTG repeat is preceded by a polymorphic but stable CTA tract, with the configuration (CTA)(1-21)(CTG)(n). The CTG portion of the repeat is elongated on pathogenic alleles, which nearly always change in size when transmitted from generation to generation. To better understand the reduced penetrance and maternal penetrance bias associated with SCA8 we analyzed the sequence configurations and instability patterns of the CTG repeat in affected and unaffected family members. In contrast to other triplet repeat diseases, expanded alleles found in affected SCA8 individuals can have either a pure uninterrupted CTG repeat tract or an allele with one or more CCG, CTA, CTC, CCA or CTT interruptions. Surprisingly, we found six different sequence configurations of the CTG repeat on expanded alleles in a seven generation family. In two instances duplication of CCG interruptions occurred over a single generation and in other instances duplications that had occurred in different branches of the family could be inferred. We also evaluated SCA8 instability in sperm samples from individuals with expansions ranging in size from 80 to 800 repeats in blood. Surprisingly the SCA8 repeat tract in sperm underwent contractions, with nearly all of the resulting expanded alleles having repeat lengths of <100 CTGs, a size that is not often associated with disease. These en masse repeat contractions in sperm likely underlie the reduced penetrance associated with paternal transmission.

Alleles↗
PubMed2000

CAG repeat length in RAI1 is associated with age at onset variability in spinocerebellar ataxia type 2 (SCA2).

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant disorder caused by the expansion of a polymorphic (CAG)(n) tract, which is translated into an expanded polyglutamine tract in the ataxin-2 protein. Although repeat length and age at disease onset are inversely related, approximately 50% of the age at onset variance in SCA2 remains unexplained. Other familial factors have been proposed to account for at least part of this remaining variance in the polyglutamine dis-orders. The ability of polyglutamine tracts to interact with each other, as well as the presence of intra-nuclear inclusions in other polyglutamine disorders, led us to hypothesize that other CAG-containing proteins may interact with expanded ataxin-2 and affect the rate of protein accumulation, and thus influence age at onset. To test this hypothesis, we used step-wise multiple linear regression to examine 10 CAG-containing genes for possible influences on SCA2 age at onset. One locus, RAI1, contributed an additional 4.1% of the variance in SCA2 age at onset after accounting for the effect of the SCA2 expanded repeat. This locus was further studied in SCA3/Machado-Joseph disease (MJD), but did not have an effect on SCA3/MJD age at onset. This result implicates RAI1 as a possible contributor to SCA2 neurodegeneration and raises the possibility that other CAG-containing proteins may play a role in the pathogenesis of other polyglutamine disorders.

Age of Onset↗
PubMed2000

The SCA8 transcript is an antisense RNA to a brain-specific transcript encoding a novel actin-binding protein (KLHL1).

Spinocerebellar ataxia type 8 (SCA8) is a neurodegenerative disorder caused by the expansion of a CTG trinucleotide repeat that is transcribed as part of an untranslated RNA. As a step towards understanding the molecular pathology of SCA8, we have defined the genomic organization of the SCA8 RNA transcripts and assembled a 166 kb segment of genomic sequence containing the repeat. The most striking feature of the SCA8 transcripts is that the most 5' exon is transcribed through the first exon of another gene that is transcribed in the opposite orientation. This gene arrangement suggests that the SCA8 transcript is an endogenous antisense RNA that overlaps the transcription and translation start sites as well as the first splice donor sequence of the sense gene. The sense transcript encodes a 748 amino acid protein with a predicted domain structure typical of a family of actin-organizing proteins related to the Drosophila Kelch gene, and so has been given the name Kelch-like 1 (KLHL1). We have identified the full-length cDNA sequence for both the human and mouse KLHLI genes, and have elucidated the general genomic organization of the human gene. The predicted open reading frame and promoter region are highly conserved, and both genes are primarily expressed in specific brain tissues, including the cerebellum, the tissue most affected by SCA8. Transfection studies with epitope-tagged KLHL1 demonstrate that the protein localizes to the cytoplasm, suggesting that it may play a role in organizing the actin cytoskeleton of the brain cells in which it is expressed.

Alternative Splicing↗
PubMed1999

A nonpathogenic GAAGGA repeat in the Friedreich gene: implications for pathogenesis.

An individual with late-onset ataxia was found to be heterozygous for an unusual (GAAGGA)65 sequence and a normal GAA repeat in the frataxin gene. No frataxin point mutation was present, excluding a form of Friedreich ataxia. (GAAGGA)65 did not have the inhibitory effect on gene expression in transfected cells shown by pathogenic GAA repeats of similar length. GAA repeats, but not (GAAGGA)65, adopt a triple helical conformation in vitro. We suggest that such a triplex structure is essential for suppression of gene expression.

Aged↗
PubMed1999

Clinical and genetic characteristics of a five-generation family with a novel form of myotonic dystrophy (DM2).

We report the clinical and genetic characteristics of a five-generation family (MN1) with an unusual form of myotonic dystrophy (DM). Affected individuals have clinical features that are similar to DM including myotonia, distal weakness, frontal balding, polychromatic cataracts, infertility and cardiac arrhythmias. Genetic analyses reveal that affected individuals do not have the CTG expansion associated with DM, nor is the disease locus linked to the DM region of chromosome 19. We have also excluded the MN1 disease locus from the chromosomal regions containing the genes for the muscle sodium (alpha- and beta-subunits) and chloride channels, both of which are involved in other myotonic disorders. We have recently mapped the disease locus (DM2) in this family to a 10 cM region of chromosome 3q [Ranum LPW, Rasmussen PF, Benzow KA, Koob MD, Day JW. Nat Genet 1998;19:196-198]. The genetically distinct form of myotonic dystrophy in the MN1 kindred shares some of the clinical features of previously reported families with proximal myotonic myopathy (PROMM). The size of the MN1 family (25 affected individuals) makes it a unique resource for both clinical and genetic studies. This second form of myotonic dystrophy may help resolve the confusion that remains about how the CTG repeat expansion in the 3' untranslated portion of the myotonin protein kinase gene causes the multisystem involvement of DM.

Adolescent↗
PubMed1999

An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8)

Myotonic dystrophy (DM) is the only disease reported to be caused by a CTG expansion. We now report that a non-coding CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). This expansion, located on chromosome 13q21, was isolated directly from the genomic DNA of an ataxia patient by RAPID cloning. SCA8 patients have expansions similar in size (107-127 CTG repeats) to those found among adult-onset DM patients. SCA8 is the first example of a dominant SCA not caused by a CAG expansion translated as a polyglutamine tract.

Alleles↗
PubMed1999

Nuclear localization of the spinocerebellar ataxia type 7 protein, ataxin-7.

Spinocerebellar ataxia type 7 (SCA7) belongs to a group of neurological disorders caused by a CAG repeat expansion in the coding region of the associated gene. To gain insight into the pathogenesis of SCA7 and possible functions of ataxin-7, we examined the subcellular localization of ataxin-7 in transfected COS-1 cells using SCA7 cDNA clones with different CAG repeat tract lengths. In addition to a diffuse distribution throughout the nucleus, ataxin-7 associated with the nuclear matrix and the nucleolus. The location of the putative SCA7 nuclear localization sequence (NLS) was confirmed by fusing an ataxin-7 fragment with the normally cytoplasmic protein chicken muscle pyruvate kinase. Mutation of this NLS prevented protein from entering the nucleus. Thus, expanded ataxin-7 may carry out its pathogenic effects in the nucleus by altering a matrix-associated nuclear structure and/or by disrupting nucleolar function.

Animals↗
PubMed1998

Genetic mapping of a second myotonic dystrophy locus.

We report the mapping of a second myotonic dystrophy locus, myotonic dystrophy type 2 (DM2). Myotonic dystrophy (DM) is a multi-system disease and the most common form of muscular dystrophy in adults. In 1992, DM was shown to be caused by an expanded CTG repeat in the 3' untranslated region of the dystrophia myotonica-protein kinase gene (DMPK) on chromosome 19 (refs 2-6). Although several theories have been put forth to explain how the CTG expansion causes the broad spectrum of clinical features associated with DM, it is not understood how this mutation, which does not alter the protein-coding region of a gene, causes an affect at the cellular level. We have identified a five-generation family (MN1) with a genetically distinct form of myotonic dystrophy. Affected members exhibit remarkable clinical similarity to DM (myotonia, proximal and distal limb weakness, frontal balding, cataracts and cardiac arrhythmias) but do not have the chromosome-19 D CTG expansion. We have mapped the disease locus (DM2) of the MN1 family to a 10-cM region of chromosome 3q. Understanding the common molecular features of two different forms of the disease should shed light on the mechanisms responsible for the broad constellation of seemingly unrelated clinical features present in both diseases.

Adult↗
PubMed1998

Rapid cloning of expanded trinucleotide repeat sequences from genomic DNA.

Trinucleotide repeat expansions have been shown to cause a number of neurodegenerative diseases. A hallmark of most of these diseases is the presence of anticipation, a decrease in the age at onset in consecutive generations due to the tendency of the unstable trinucleotide repeat to lengthen when passed from one generation to the next. The involvement of trinucleotide repeat expansions in a number of other diseases--including familial spastic paraplegia, schizophrenia, bipolar affective disorder and spinocerebellar ataxia type 7 (SCA7; ref. 10)--is suggested both by the presence of anticipation and by repeat expansion detection (RED) analysis of genomic DNA samples. The involvement of trinucleotide expansions in these diseases, however, can be conclusively confirmed only by the isolation of the expansions present in these populations and detailed analysis to assess each expansion as a possible pathogenic mutation. We describe a novel procedure for quick isolation of expanded trinucleotide repeats and the corresponding flanking nucleotide sequence directly from small amounts of genomic DNA by a process of Repeat Analysis, Pooled Isolation and Detection of individual clones containing expanded trinucleotide repeats (RAPID cloning). We have used this technique to clone the pathogenic SCA7 CAG expansion from an archived DNA sample of an individual affected with ataxia and retinal degeneration.

Ataxia↗
PubMed1998

Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families.

OBJECTIVE: To determine the incidence of spinocerebellar ataxia (SCA) types 1, 2, 3, 6, and 7 and Friedreich's ataxia (FA) among a large panel of ataxia families. BACKGROUND: The ataxias are a clinically and genetically heterogeneous group of neurodegenerative diseases that variably affect the cerebellum, brainstem, and spinocerebellar tracts. Trinucleotide repeat expansions have been shown to be the mutational mechanism for five dominantly inherited SCAs as well as FA. METHODS: We collected DNA samples and clinical data from patients representing 361 families with adult-onset ataxia of unknown etiology. Patients with a clinical diagnosis of FA were specifically excluded from our collection. RESULTS: Among the 178 dominant kindreds, we found SCA1 expansion at a frequency of 5.6%, SCA2 expansion at a frequency of 15.2%, SCA3 expansion at a frequency of 20.8%, SCA6 expansion at a frequency of 15.2%, and SCA7 expansion at a frequency of 4.5%. FA alleles were found in 11.4% of apparently recessive and 5.2% of apparently sporadic patients. Among these patients the repeat sizes for one or both FA alleles were relatively small, with sizes for the smaller allele ranging from 90 to 600 GAA repeats. The clinical presentation for these patients is atypical for FA, with one or more of the following characteristics: adult onset of disease, retained tendon reflexes, normal plantar response, and intact or partially intact sensory perceptions. CONCLUSIONS: Pathogenic trinucleotide repeat expansions were found among 61% of the dominant kindreds. Among patients with apparently recessive or negative family histories of ataxia, 6.8% and 4.4% tested positive for a CAG expansion at one of the dominant loci, and 11.4 and 5.2% of patients with apparently recessive or sporadic forms of ataxia had FA expansions. Because of the significant implications that a dominant versus recessive inheritance pattern has for future generations, it is important to screen patients who do not have a clearly dominant inheritance pattern for expansions at both the FA and the dominant ataxia loci.

Adult↗
PubMed1995

Spinocerebellar ataxia type 1 and Machado-Joseph disease: incidence of CAG expansions among adult-onset ataxia patients from 311 families with dominant, recessive, or sporadic ataxia.

The ataxias are a complex group of diseases with both environmental and genetic causes. Among the autosomal dominant forms of ataxia the genes for two, spinocerebellar ataxia type 1 (SCA1) and Machado-Joseph disease (MJD), have been isolated. In both of these disorders the molecular basis of disease is the expansion of an unstable CAG trinucleotide repeat. To assess the frequency of the SCA1 and MJD trinucleotide repeat expansions among individuals diagnosed with ataxia we have collected DNA from individuals representing 311 families with adult-onset ataxia of unknown etiology and screened these samples for trinucleotide repeat expansions within the SCA1 and MJD genes. Within this group there are 149 families with dominantly inherited ataxia. Of these, 3% had SCA1 trinucleotide repeat expansions, whereas 21% were positive for the MJD trinucleotide expansion. Thus, together SCA1 and MJD represent 24% of the autosomal dominant ataxias in our group, and the frequency of MJD is substantially greater than that of SCA1. For the 57 patients with MJD trinucleotide repeat expansions, a strong inverse correlation between CAG repeat size and age at onset was observed (r = -.838). Among the MJD patients, the normal and affected ranges of CAG repeat size are 14-40 and 68-82 repeats, respectively. For SCA1 the normal and affected ranges are much closer, containing 19-38 and 40-81 CAG repeats, respectively.

Adult↗
PubMed1994

Spinocerebellar ataxia type 5 in a family descended from the grandparents of President Lincoln maps to chromosome 11.

Autosomal dominant ataxias are a genetically heterogeneous group of disorders for which spinocerebellar ataxia (SCA) loci on chromosomes 6p, 12q, 14q and 16q have been reported. We have examined 170 individuals (56 of whom were affected) from a previously unreported ten-generation kindred with a dominant ataxia that is clinically and genetically distinct from those previously mapped. The family has two major branches which both descend from the paternal grandparents of President Abraham Lincoln. Among those examined, 56 individuals have a generally non-life threatening cerebellar ataxia. Disease onset varies from 10-68 years and anticipation is evident. We have mapped this gene, spinocerebellar ataxia type 5 (SCA5), to the centromeric region of chromosome 11.

Adolescent↗
PubMed1994

Molecular and clinical correlations in spinocerebellar ataxia type I: evidence for familial effects on the age at onset.

The spinocerebellar ataxias are a group of debilitating neurodegenerative diseases for which a clinical classification system has proved unreliable. We have recently isolated the gene for spinocerebellar ataxia type 1 (SCA1) and have shown that the disease is caused by an expanded, unstable, CAG trinucleotide repeat within an expressed gene. Normal alleles have a size range of 19-36 repeats, while SCA1 alleles have 42-81 repeats. In this study, we examined the frequency and variability of the SCA1 repeat expansion in 87 kindreds with diverse ethnic backgrounds and dominantly inherited ataxia. All nine families for which linkage to the SCA1 region of 6p had previously been established showed repeat expansion, while 3 of the remaining 78 showed a similar abnormality. For 113 patients from the families with repeat expansion, inverse correlations between CAG repeat size and both age at onset and disease duration were observed. Repeat size accounted for 66% of the variation in age at onset in these patients. After correction for repeat size, interfamilial differences in age at onset remained significant, suggesting that additional genetic factors affect the expression of the SCA1 gene product.

Adolescent↗
PubMed1993

Mapping and cloning of the critical region for the spinocerebellar ataxia type 1 gene (SCA1) in a yeast artificial chromosome contig spanning 1.2 Mb.

The gene responsible for spinocerebellar ataxia type 1 (SCA1) has been localized to a 6.7-cM region between the centromeric marker D6S109 and the telomeric marker D6S89. We screened two yeast artificial chromosome (YAC) libraries using sequence-tagged sites at D6S89 and at newly identified markers in 6p22-p23. Fifty YAC clones were identified and 34 insert termini were isolated from some of these YACs for detailed overlap mapping and long-range restriction analysis. A large YAC contig estimated to span 2.5 Mb was developed and genetic analysis in five large SCA1 kindreds using highly informative dinucleotide repeat polymorphisms mapped to this contig allowed the identification of D6S274 as the closest centromeric flanking marker for SCA1. Long-range restriction analysis determined the size for the critical SCA1 region, as defined by the two flanking markers D6S274 and D6S89, to be 1.2 Mb. This region is spanned by a minimum set of four nonchimeric YAC clones. The development of a 2.5-Mb YAC contig in 6p22-p23 provides valuable reagents for characterization of this genomic region and for the cloning of the SCA1 gene.

Animals↗
PubMed1993

Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant disorder characterized by neurodegeneration of the cerebellum, spinal cord and brainstem. A 1.2-Megabase stretch of DNA from the short arm of chromosome 6 containing the SCA1 locus was isolated in a yeast artificial chromosome contig and subcloned into cosmids. A highly polymorphic CAG repeat was identified in this region and was found to be unstable and expanded in individuals with SCA1. There is a direct correlation between the size of the (CAG)n repeat expansion and the age-of-onset of SCA1, with larger alleles occurring in juvenile cases. We also show that the repeat is present in a 10 kilobase mRNA transcript. SCA1 is therefore the fifth genetic disorder to display a mutational mechanism involving an unstable trinucleotide repeat.

Base Sequence↗