Margaret J. Kovach

Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein

Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) is a dominant progressive disorder that maps to chromosome 9p21.1–p12. We investigated 13 families with IBMPFD linked to chromosome 9 using a candidate-gene approach. We found six missense mutations in the gene encoding valosin-containing protein (VCP, a member of the AAA-ATPase superfamily) exclusively in all 61 affected individuals. Haplotype analysis indicated that descent from two founders in two separate North American kindreds accounted for IBMPFD in ∼50% of affected families. VCP is associated with a variety of cellular activities, including cell cycle control, membrane fusion and the ubiquitin-proteasome degradation pathway. Identification of VCP as causing IBMPFD has important implications for other inclusion-body diseases, including myopathies, dementias and Paget disease of bone (PDB), as it may define a new common pathological ubiquitin-based pathway.

Clinical and molecular studies in a unique family with autosomal dominant limb-girdle muscular dystrophy and Paget disease of bone

Purpose: To characterize the clinical features and perform linkage analysis of candidate loci in a large Illinois family with autosomal dominant limb-girdle muscular dystrophy (LGMD) and Paget disease of bone (PDB).Methods: The family includes 11 affected individuals (8 M, 3 F). Clinical, biochemical and radiologic evaluations were performed to delineate clinical features of the disorder. Linkage analysis with polymorphic markers was performed for previously identified LGMD, PDB and cardiomyopathy loci.Results: Onset of PDB is early, at a mean age of 35 y, with classic distribution involving the spine, pelvis, and skull. Muscle weakness and atrophy is progressive with mildly elevated to normal creatine phosphokinase levels. Muscle biopsy in the oldest male revealed vacuolated fibers, however, in others revealed nonspecific myopathy. Affected individuals die from progressive muscle weakness, and respiratory and cardiac failure in their 40s-60s. Linkage analysis excluded autosomal dominant and recessive LGMD, PDB, and cardiomyopathy loci.Conclusion: Autosomal dominant LGMD associated with PDB is an unusual disorder. Linkage analysis indicates a unique locus in this family.

A Unique Point Mutation in the PMP22 Gene Is Associated with Charcot-Marie-Tooth Disease and Deafness

Charcot-Marie-Tooth disease (CMT) with deafness is clinically distinct among the genetically heterogeneous group of CMT disorders. Molecular studies in a large family with autosomal dominant CMT and deafness have not been reported. The present molecular study involves a family with progressive features of CMT and deafness, originally reported by Kousseff et al. Genetic analysis of 70 individuals (31 affected, 28 unaffected, and 11 spouses) revealed linkage to markers on chromosome 17p11.2-p12, with a maximum LOD score of 9.01 for marker D17S1357 at a recombination fraction of .03. Haplotype analysis placed the CMT-deafness locus between markers D17S839 and D17S122, a approximately 0.6-Mb interval. This critical region lies within the CMT type 1A duplication region and excludes MYO15, a gene coding an unconventional myosin that causes a form of autosomal recessive deafness called DFNB3. Affected individuals from this family do not have the common 1.5-Mb duplication of CMT type 1A. Direct sequencing of the candidate peripheral myelin protein 22 (PMP22) gene detected a unique G-->C transversion in the heterozygous state in all affected individuals, at position 248 in coding exon 3, predicted to result in an Ala67Pro substitution in the second transmembrane domain of PMP22.

Genetic heterogeneity in autosomal dominant essential tremor

Purpose: To perform linkage analysis of candidate loci in a large Midwestern family with autosomal dominant essential tremor.Methods: Thirty-eight members of a six-generation family were evaluated for essential tremor using consensus criteria. Linkage analysis was performed with microsatellite markers reported for three genetic loci associated with familial essential tremor.Results: Patients exhibited a combination of postural and kinetic tremor involving primarily the arms and hands, with a mean age of onset of 31 years. Genetic studies excluded linkage to ETM1 and ETM2 loci, as well as a candidate locus for parkinsonism and postural tremor on chromosome 4p.Conclusion: Familial essential tremor is a common hereditary movement disorder demonstrating phenotypic variability and genetic heterogeneity.

Clinical and genetic heterogeneity in chromosome 9p associated hereditary inclusion body myopathy: exclusion of GNE and three other candidate genes

We have previously reported a new autosomal dominant inclusion body myopathy clinically resembling limb girdle muscular dystrophy, associated with Paget disease of bone in the majority and frontotemporal dementia in a third of individuals. The critical locus for this unique disorder now termed IBMPFD is 9 p21.1-p12, spans 5.5 Mb and contains the gene responsible for the recessive quadriceps-sparing inclusion body myopathy (IBM2). Mutation analysis of the GNE gene associated with IBM2 in affected individuals from four IBMPFD families did not identify any mutations, indicating that the two disorders are not allelic. Expression studies indicate that GNE has a tissue-specific splice pattern, with four splice variants. Mutation analysis in three other candidate genes (beta-tropomyosin, NDUFB6 and SMU1) did not identify any mutations.

Manifestations in four males with and an obligate carrier of the Lenz microphthalmia syndrome

Lenz microphthalmia syndrome is a rare X-linked recessive condition first described by Lenz in 1955 and comprises of anophthalmia, microcephaly, mental retardation, external ear, digital, cardiac, skeletal, and urogenital anomalies. We present three brothers (ages 15 years, 9 years, and 18 months) and a maternal uncle (age 27 years) with congenital anophthalmia, delayed motor development, hypotonia, and moderate to severe mental retardation. They also have abnormally modeled ears, high-arched palate, pectus excavatum, finger and toe syndactyly, clinodactyly, fetal pads, scoliosis, cardiac, and renal abnormalities. An obligate carrier had abnormally modeled ears and syndactyly of the 2nd to 3rd toes bilaterally. Linkage and haplotype analysis in this family indicates that the gene is located in a 17.65-cM region on chromosome region Xq27-Xq28.

Site-specific Photo-cross-linking between λ Integrase and Its DNA Recombination Target

The site-specific recombinase (Int) of bacteriophage λ is a heterobivalent DNA-binding protein and is composed of three domains as follows: an amino-terminal domain that binds with high affinity to “arm-type” sequences within the recombination target DNA (att sites), a carboxyl-terminal domain that contains all of the catalytic functions, and a central domain that contributes significantly to DNA binding at the “core-type” sequences where DNA cleavage and ligation are executed. We constructed a family of core-type DNA oligonucleotides, each of which contained the photoreactive analog 4-thiodeoxythymidine (4-thioT) at a different position. When tested for their respective abilities to promote covalent cross-links with Int after irradiation with UV light at 366 nm, one oligonucleotide stood out dramatically. The 4-thioT substitution on the DNA strand opposite the site of Int cleavage led to photo-induced cross-linking efficiencies of ∼20%. The efficiency and specificity of Int binding and cleavage at this 4-thioT-substituted core site was shown to be largely uncompromised, and its ability to participate in a full site-specific recombination reaction was reduced only slightly. Identification of the photo-cross-linked residue as Lys-141 in the central domain provides, along with other results, several insights about the nature of core-type DNA recognition by the bivalent recombinases of the λ Int family.

Clinical heterogeneity in autosomal dominant optic atrophy in two 3q28-qter linked central Illinois families

Purpose: To examine the clinical and genetic heterogeneity of autosomal dominant optic atrophy among two unrelated central Illinois families.Methods: Forty-three individuals from two pedigrees had complete eye examinations. Linkage analysis was performed with microsatellite markers from the region 3q28–29.Results: Visual acuity in 21 affected individuals ranged from 20/25 to 20/800. Vision loss was more severe in males than females (P = 0.02). Color vision testing revealed generalized dyschromatopsia. Both visual acuity and color vision deteriorated with age. Linkage was established to chromosome 3q28–29 (LODmax = 4.68 for D3S2305).Conclusion: Autosomal dominant optic atrophy linked to chromosome 3q28–29 shows intrafamilial phenotypic variation as well as sex-influenced severity in two Midwestern families.

Clinical and Molecular Studies in a large unique family with Limb-Girdle Muscular Dystrophy and Paget Disease of Bone

A large Central Illinois family with Limb-Girdle Muscular Dystrophy (LGMD)and Paget disease of bone (PDB) includes 9 affected individuals (6 M, 3 F) ranging in ages from 33 y to 64 y Onset of the disorder is early, at a mean age of 35 y with bone pain in the hips, shoulders and back, weakness and atrophy of the hip and shoulder girdle muscles, and absent or reduced deep-tendon reflexes. Laboratory investigation in the affected individuals indicates elevated alkaline phosphatase (mean 455, range 93-1508 (normal 30-130 mg/dl), and CPK levels (mean 273, range 60-1145 (20-222 mg/dl). High-resolution karyotype did not identify a microdeletion syndrome. Muscle biopsies in 5 individuals revealed non-specific myopathy with vacuolar myopathy only seen in the oldest male Affected individuals die prematurely from progressive muscle weakness, cardiomyopathy and cardiac failure in the forties to sixties.LGMD encompasses a genetically and clinically diverse group of disorders. Twenty-two genetic loci were excluded in this family by linkage analysis performed in 9 affecteds. 13 unaffecteds and 1 spouse with 4 autosomal dominant and 8 autosomal recessive LGMD loci, the Edstrom myopathy and ALS loci. 2 Paget disease loci and 6 cardiomyopathy loci, thus supporting our hypothesis that this family displays a genetically distinct disorder. Linkage anaKsis of haplotype data generated by Marshfietd genotyping Center will be presentedReview of the literature repeals three similar associations of neuromuscular and Pager disease Caughey et al (1957) described a family suffering from dystrophia myotonica and familial PDB. Tucker et al (1982) identified a family with autosomal dominant amyotrophic lateral sclerosis and PDB. and McBride et al (1966) found an association of PDB and a limb girdle type of muscular dsstrophv in four of si\ siblings Early demise from cardiormopathy was not a feature in these families Paget disease is known to cause high output cardiac failure and may therefore be contributing to the early demise if untreated Treatment of Panel disease is very successful with bisphosphonates A treatment protocol with risedronate, coenzyme Q and antioxidants is in progress to evaluate the ettects on Paget, muscular dystrophy and cardiomyopathy Identification of the specific gene mutation, however, may permit more specifit treatment protocols