Joseph J. Higgins

Mapping of a Gene for Parkinson's Disease to Chromosome 4q21-q23

Parkinsons disease (PD) is the second most common neurodegenerative disorder after Alzheimers disease, affecting approximately 1 percent of the population over age 50. Recent studies have confirmed significant familial aggregation of PD and a large number of large multicase families have been documented. Genetic markers on chromosome 4q21-q23 were found to be linked to the PD phenotype in a large kindred with autosomal dominant PD, with a Zmax = 6.00 for marker D4S2380. This finding will facilitate identification of the gene and research on the pathogenesis of PD.

A mutation in a novel ATP-dependent Lon protease gene in a kindred with mild mental retardation

Background: Identifying the genetic factors that contribute to memory and learning is limited by the complexity of brain development and the lack of suitable human models for mild disorders of cognition. Methods: Previously, a disease locus was mapped for a mild type of nonsyndromic mental retardation (IQ between 50 and 70) to a 4.2-MB interval on chromosome 3p25-pter in a large kindred. The genes and transcripts within the candidate region were systematically analyzed for mutations by single-strand polymorphism analysis and DNA sequencing. Results: A nonsense mutation causing a premature stop codon in a novel gene (cereblon; CRBN) was identified that encodes for an ATP-dependent Lon protease. The predicted protein sequence is highly conserved across species, and it belongs to a family of proteins that selectively degrade short-lived polypeptides and regulate mitochondrial replication and transcription. One member of the Lon-containing protein family is regionally expressed in the human hippocampus, an important neuroanatomic region that is involved in long-term potentiation and learning. The mutation in the CRBN gene described interrupts an N-myristoylation site and eliminates a casein kinase II phosphorylation site at the C terminus. Conclusions: A gene on chromosome 3p that is associated with mild mental retardation in a large kindred is reported. This finding implicates a role for the ATP-dependent degradation of proteins in memory and learning.

Progressive supranuclear gaze palsy is in linkage disequilibrium with theτ and not the α-synuclein gene

We studied two candidate genes, tau (τ) and α-synuclein (SNCA), for evidence of linkage disequilibrium on a group of unrelated individuals with progressive supranuclear palsy (PSP) and a group of age-matched control subjects. The τ a1 allele and the τ a1a1 genotype were overrepresented in individuals with PSP and the τ polymorphism was in linkage disequilibrium with the PSP disease locus when a recessive inheritance model was employed. We also report a lack of evidence to support linkage disequilibrium between PSP and the SNCA candidate Parkinsons disease gene on chromosome 4q21-q23.

A variant in the HS1-BP3 gene is associated with familial essential tremor

Background: Genetic linkage studies have identified two susceptibility loci for essential tremor (ET) on chromosomes 3q13 (ETM1) and 2p24.1 (ETM2). Linkage disequilibrium studies in separate population samples from the United States and Singapore suggest an association between ET and loci at ETM2. Methods: Fine mapping studies were conducted on multiplex and singleton US families linked to ETM2 using newly detected loci within the candidate interval to establish the minimal critical region (MCR) harboring an ET gene. The genes and transcripts within this interval were systematically analyzed by single-strand conformational polymorphism analysis and DNA sequencing. Results: A 464-kb region between loci D2S2150 and etm1231 was defined as the MCR. The coding regions and flanking intronic splice sites of two genes and seven transcripts in this interval were evaluated for mutations. A missense mutation (828C→G) in the transcript FLJ14249 (HS1-BP3) was identified in one US family. This mutation was found in another apparently unrelated US family with ET and was absent in 150 control samples (300 chromosomes). The 828C→G mutation causes a substitution of a glycine for an alanine residue in the HS1-BP3 protein. The HS1-BP3 protein binds to proteins that are highly expressed in motor neurons and Purkinje cells and regulate the Ca2+/calmodulin-dependent protein kinase activation of tyrosine and tryptophan hydroxylase. Conclusions: A rare variant in the HS1-BP3 gene that is associated with essential tremor (ET) in two families is reported. This finding will facilitate research on the functional role of this gene and related genes in the pathogenesis of ET.

An extended 5′-tau susceptibility haplotype in progressive supranuclear palsy

Objective: To confirm the association of an extended 5′-tau haplotype on chromosome 17q with the disease phenotype in clinically ascertained individuals with sporadic progressive supranuclear palsy (PSP). Background: PSP is a neurodegenerative disease with parkinsonian signs accompanied by vertical supranuclear palsy and tau pathologic features. Previously, we documented the complete segregation of an extended 5′-tau haplotype consisting of four single nucleotide polymorphisms (SNP) with the disease phenotype in sporadic PSP. This study was conducted in an independent cohort to confirm these results and to improve the statistical power of the data. Design and Methods: Direct sequencing and restriction enzyme digests were used to analyze four SNP in tau Exons 1, 4A, and 8. These contiguous SNP were used to reconstruct an extended 5′-tau haplotype in 52 affected and 54 age-matched control individuals. Results: The four SNP formed two homozygous 5′-tau haplotypes (HapA and HapC) or a heterozygous genotype. Fifty-one (98%) patients with PSP had HapA; one (2%) with a later onset was heterozygous; and none had HapC. These PSP haplotype frequencies were different (p < 0.00001) from those of the age-matched control group, in which 18 (33%) people had HapA; 26 (48%) were heterozygous; and 10 (19%) had HapC. The extended 5′-tau haplotype, HapA, had a high sensitivity (98%) and a moderate specificity (67%) as a marker for PSP. Conclusions: A 5′-tau susceptibility haplotype may be a sensitive marker for sporadic PSP and a genetic defect in, or closely linked to, tau may contribute to the cause of PSP.

Mutations in American families with spinocerebellar ataxia (SCA) type 3 SCA3 is allelic to Machado-Joseph disease

Article abstract-We identified an expansion of the CAG trinucleotide repeat in the coding region of the Machado-Joseph disease gene in 7 of 24 American families diagnosed with autosomal dominant ataxia. All affected individuals were heterozygous for an expanded allele that ranged from 67 to more than 200 CAG repeats, whereas the normal allele had 14 to 33 repeats. In contrast to the Azorean-Portuguese origins of Machado-Joseph disease, the two largest American families were of German and Dutch-African descent. Clinical, pathologic, and genetic evaluations suggest that American families with spinocerebellar ataxia type 3 differ from those with Machado-Joseph disease by their ethnic origins, predominant spinopontine atrophy, lack of dystonic features, and larger CAG repeat expansion. NEUROLOGY 1996;46: 208-213

Preserved cognitive processes in cerebellar degeneration

Aspects of cognitive processing in patients with cerebellar degeneration (CD) were studied in order to examine the validity of recent findings that CD patients demonstrate deficits in visuospatial cognition and verbal-associative learning. Two groups of patients with CD were compared to stratified matched control groups on tests examining selective visual attention, visual spatial attention, mental rotation of geometric designs, and memory for the temporal order of words they were previously exposed to. CD patients performed similarly to their matched controls across all tasks. These results indicate that the reported cognitive deficits of CD patients are quite selective and need further specification in order to more fully describe their relationship to cerebellar dysfunction.

State of the art review: Molecular diagnosis of inherited movement disorders. Movement Disorders Society task force on molecular diagnosis

This review is designed to provide practical help for the clinical neurologist to make appropriate use of the possibilities of molecular diagnosis of inherited movement disorders. Huntingtons disease, Parkinsons disease and parkinsonian syndromes, ataxias, Wilson disease, essential tremor, dystonias, and other genetic diseases associated with a variety of movement disorders are considered separately.

HS1-BP3 gene variant is common in familial essential tremor.

Essential tremor (ET) is a movement disorder characterized by a postural or kinetic tremor of the hands, head, or voice. It is typically a familial condition and affects 1% to 4% of the general population. The trait is genetically linked to chromosome 2p in some families. A variant (828C→G) in exon 7 of the hematopoietic‐specific protein 1 binding protein 3 gene (HS1‐BP3) on chromosome 2p recently has been found to segregate with ET in 2 families. To determine the frequency of this variant in a larger series, we studied patients with ET, Parkinson disease (PD), and controls without tremor. Affected singletons representing 73 families from the United States with dominantly inherited ET, 35 individuals with PD, and 304 healthy controls older than age 60 were tested for the 828C→G variant in exon 7 of the HS1‐BP3 gene by a BseYI restriction enzyme digest of the polymerase chain reaction product. Heterozygous carriers of the mutant allele were identified in 12 individuals with ET (16.4%) and in 1 individual with PD and postural tremor (3%). All of the healthy controls (608 chromosomes) were homozygous for the wild‐type allele. The 828C→G genetic variant in the HS1‐BP3 gene occurs relatively frequently in subjects with ET. The variant may also be found in some individuals with PD and postural tremor. The HS1‐BP3 gene plays a putative role in regulating catecholamine and serotonin metabolism, but the functional consequences of the amino acid substitution (A265G) caused by this genetic variant is unknown.

Candidate genes for recessive non-syndromic mental retardation on chromosome 3p (MRT2A).

A mild type of autosomal recessive, non‐syndromic mental retardation (NSMR) is linked to loci on chromosome 3p. This report delimits the MRT2A minimal critical region to 4.2 Mb between loci D3S3630 and D3S1304. This interval contains nine genes (IL5RA, TRNT1, LRRN1, SETMAR, SUMF1, ITPR1, BHLHB2, EDEM, and MRPS36P1). The results suggest that a mutation does not exist in these genes and that an unknown transcript in the region contributes to the cognitive deficits in NSMR.