Pathology - Journal Articles

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    Phenotypic variation in a caucasian kindred with chorea-acanthocytosis
    (Wiley, 2014-12-06) Merwick, Áine; Mok, Tzehow; McNamara, Brian; Parfrey, Nollaig A.; Moore, Helena; Sweeney, Brian J.; Hand, Collette K.; Ryan, Aisling M.; University College Cork
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    A novel locus for restless legs syndrome maps to chromosome 19p in an Irish pedigree
    (Springer, 2021-03-14) Skehan, Evelyn B.; Abdulrahim, Manal M. A.; Parfrey, Nollaig A.; Hand, Collette K.
    Restless legs syndrome (RLS) is a common, sleep-related movement disorder. The symptoms follow a circadian pattern, worsening in the evening or night, leading to sleep disruption and daytime somnolence. Familial forms of RLS have been described and usually display an autosomal dominant pattern of inheritance. To date, linkage analysis has identified nine RLS loci, but no specific causative gene has been reported. Association mapping has highlighted a further four genomic areas of interest. We have conducted a genome-wide linkage analysis in an Irish autosomal dominant RLS pedigree with 11 affected members. Significant linkage was found on chromosome 19p for a series of microsatellite markers, with a maximum two-point LOD score of 3.59 at θ = 0.0 for marker D19S878. Recombination events, identified by haplotype analysis, define a genetic region of 6.57 cM on chromosome 19p13.3, corresponding to an interval of 2.5 Mb. This study provides evidence of a novel RLS locus and provides further evidence that RLS is a genetically heterogenous disorder.
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    A novel ATP1A2 gene mutation in an Irish familial hemiplegic migraine kindred
    (Wiley, 2008-01) Fernandez, Desiree M.; Hand, Collette K.; Sweeney, Brian J.; Parfrey, Nollaig A.
    Objective: We studied a large Irish Caucasian pedigree with familial hemiplegic migraine (FHM) with the aim of finding the causative gene mutation. Background: FHM is a rare autosomal-dominant subtype of migraine with aura, which is linked to 4 loci on chromosomes 19p13, 1q23, 2q24, and 1q31. The mutations responsible for hemiplegic migraine have been described in the CACNA1A gene (chromosome 19p13), ATP1A2 gene (chromosome 1q23), and SCN1A gene (chromosome 2q24). Methods: We performed linkage analyses in this family for chromosome 1q23 and performed mutation analysis of the ATP1A2 gene. Results: Linkage to the FHM2 locus on chromosome 1 was demonstrated. Mutation screening of the ATP1A2 gene revealed a G to C substitution in exon 22 resulting in a novel protein variant, D999H, which co-segregates with FHM within this pedigree and is absent in 50 unaffected individuals. This residue is also highly conserved across species. Conclusions: We propose that D999H is a novel FHM ATP1A2 mutation.
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    A novel PLP1 mutation further expands the clinical heterogeneity at the locus
    (Cambridge University Press, 2012-12-02) Hand, Collette K.; Bernard, Genevieve; Dube, Marie-Pierre; Shevell, Michael I.; Rouleau, Guy A.; Canadian Institutes of Health Research; Fonds de Recherche du Québec - Santé; Réseau de Médecine Génétique Appliquée (RMGA) Québec
    Objectives: To characterize at clinical and molecular levels a family presenting with X-linked recessive Hereditary Spastic Paraplegia (HSP). Background: HSPs are a large group of genetically heterogeneous neurodegenerative disorders characterized by progressive upper motor neuron signs. Mutations in the proteolipid protein (PLP1) gene have been identified in families linked to the SPG2 locus on chromosome Xq22. However, Pelizaeus-Merzbacher disease (PMD) is also an X-linked recessive neurological disorder caused by PLP1 mutations. Methods: The SPG2 locus was investigated by linkage analysis in the family. The PLP1 gene was screened by sequencing. We present findings in a large French-Canadian family with an X-linked recessive HSP. The proband presented early with developmental delay and developed progressive spastic paraplegia. He has been wheelchair-bound since the age of three years. At the latest follow-up, he was 20 years-old and had severe spasticity predominantly affecting the lower extremities, moderate cerebellar dysfunction, and optic atrophy. Results: Linkage to SPG2 was established and a G to A mutation (MIR) in the initiation codon of the PLP1 gene was identified, likely resulting in the complete absence of proteolipid protein. Conclusions: We report a new PLP1 gene mutation in a patient with a clinical phenotype consistent with a PLP1 null syndrome.
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    Homozygous SLC4A11 mutation in a large Irish CHED2 pedigree
    (Taylor & Francis, 2016-04-08) Hand, Collette K.; McGuire, Mairide; Parfrey, Nollaig A.; Murphy, Conor C.; Hospital Saturday Fund, Ireland
    Background: Congenital hereditary endothelial dystrophy (CHED) is a genetic disorder of corneal endothelial cells resulting in corneal clouding and visual impairment. Autosomal dominant (CHED1) and autosomal recessive (CHED2) forms have been reported and map to distinct loci on chromosome 20. CHED2 is caused by mutations in the SLC4A11 gene which encodes a membrane transporter protein. Materials and methods: Members of a large CHED2 family were recruited for clinical and genetic studies. Genomic DNA was sequenced for the exons and intron-exon boundaries of the SLC4A11 gene. Results: Twelve family members were recruited, of which eight were diagnosed with CHED. A homozygous SLC4A11 mutation (Leu843Pro) was detected in the eight patients; a single copy of the mutation was present in three unaffected carriers. Conclusions: A missense SLC4A11 mutation (Leu843Pro) is responsible for CHED2 in this family; this is the first report of this mutation in a homozygous state.