Mirja Somer

Mutations in AXIN2 Cause Familial Tooth Agenesis and Predispose to Colorectal Cancer

Wnt signaling regulates embryonic pattern formation and morphogenesis of most organs. Aberrations of regulation of Wnt signaling may lead to cancer. Here, we have used positional cloning to identify the causative mutation in a Finnish family in which severe permanent tooth agenesis (oligodontia) and colorectal neoplasia segregate with dominant inheritance. Eleven members of the family lacked at least eight permanent teeth, two of whom developed only three permanent teeth. Colorectal cancer or precancerous lesions of variable types were found in eight of the patients with oligodontia. We show that oligodontia and predisposition to cancer are caused by a nonsense mutation, Arg656Stop, in the Wnt-signaling regulator AXIN2. In addition, we identified a de novo frameshift mutation 1994-1995insG in AXIN2 in an unrelated young patient with severe tooth agenesis. Both mutations are expected to activate Wnt signaling. The results provide the first evidence of the importance of Wnt signaling for the development of dentition in humans and suggest that an intricate control of Wnt-signal activity is necessary for normal tooth development, since both inhibition and stimulation of Wnt signaling may lead to tooth agenesis. Our findings introduce a new gene for hereditary colorectal cancer and suggest that tooth agenesis may be an indicator of cancer susceptibility.

Splicing Mutations of 54-bp Exons in the COL11A1 Gene Cause Marshall Syndrome, but Other Mutations Cause Overlapping Marshall/Stickler Phenotypes

Stickler and Marshall syndromes are dominantly inherited chondrodysplasias characterized by midfacial hypoplasia, high myopia, and sensorineural-hearing deficit. Since the characteristics of these syndromes overlap, it has been argued whether they are distinct entities or different manifestations of a single syndrome. Several mutations causing Stickler syndrome have been found in the COL2A1 gene, and one mutation causing Stickler syndrome and one causing Marshall syndrome have been detected in the COL11A1 gene. We characterize here the genomic structure of the COL11A1 gene. Screening of patients with Stickler, Stickler-like, or Marshall syndrome pointed to 23 novel mutations. Genotypic-phenotypic comparison revealed an association between the Marshall syndrome phenotype and splicing mutations of 54-bp exons in the C-terminal region of the COL11A1 gene. Null-allele mutations in the COL2A1 gene led to a typical phenotype of Stickler syndrome. Some patients, however, presented with phenotypes of both Marshall and Stickler syndromes.

The gene disrupted in Marinesco-Sjögren syndrome encodes SIL1, an HSPA5 cochaperone.

We identified the gene underlying Marinesco-Sjögren syndrome, which is characterized by cerebellar ataxia, progressive myopathy and cataracts. We identified four disease-associated, predicted loss-of-function mutations in SIL1, which encodes a nucleotide exchange factor for the heat-shock protein 70 (HSP70) chaperone HSPA5. These data, together with the similar spatial and temporal patterns of tissue expression of Sil1 and Hspa5, suggest that disturbed SIL1-HSPA5 interaction and protein folding is the primary pathology in Marinesco-Sjögren syndrome.

Variant Alzheimer's disease with spastic paraparesis and cotton wool plaques is caused by ps-1 mutations that lead to exceptionally high amyloid-β concentrations

We describe 3 new families affected by Alzheimers disease with spastic paraparesis. In affected individuals, including the earliest known patient with this clinical syndrome, neuropathological examination revealed large “cotton wool” plaques similar to those we have previously described in a Finnish family. In the families in which DNA was available, presenilin‐1 mutations were observed. Transfection of cells with these mutant genes caused exceptionally large increases in secreted Aβ42 levels. Furthermore, brain tissue from individuals with this syndrome had very high amyloid‐β concentrations. These findings define the molecular pathogenesis of an important subgroup of Alzheimers disease and have implications for the pathogenesis of the disease in general. Ann Neurol 2000;48:806–808

A 4-bp Deletion in the Birt-Hogg-Dubé Gene (FLCN) Causes Dominantly Inherited Spontaneous Pneumothorax

Primary spontaneous pneumothorax (PSP), a condition in which air enters the pleural space and causes secondary lung collapse, is mostly sporadic but also occurs in families. The precise etiology of PSP remains unknown, although it is associated with emphysemalike changes (bullae) in the lungs of almost all patients. We describe the results of a genetic study of a large Finnish family with a dominantly inherited tendency to PSP. A genomewide scan suggested linkage to chromosome 17p11. Screening of the best candidate gene, FLCN, revealed a 4-bp deletion in the first coding exon, which causes a frameshift that predicts a protein truncation 50 missense amino acids downstream. All carriers of the deletion had bullous lung lesions. Mutations in FLCN are also responsible for Birt-Hogg-Dubé (BHD) syndrome (a dominantly inherited disease characterized by benign skin tumors, PSP, and diverse types of renal cancer) and, rarely, are detected in sporadic renal and colorectal tumors. Unlike other FLCN mutations, the exon 4 deletion seems to be associated with bullous lung changes only with 100% penetrance. These results suggest that changes in FLCN may have an important role in the development of PSP and, more importantly, of emphysema, a chronic pulmonary disease that often leads to formation of bullous lesions and lowered pulmonary function. Additionally, given the strong association of PSP and BHD, the connection between these conditions needs to be investigated further, particularly in patients with familial PSP, who may be at a greater risk of developing renal cancer.

Variant Alzheimer’s disease with spastic paraparesis Clinical characterization

Objective: To present the clinical, neuroimaging, and electrophysiologic characteristics of a variant AD phenotype. Background: The authors have identified a large Finnish kindred with presenile dementia and spastic paraparesis due to deletion of exon 9 of presenilin 1. Neuropathologic analysis showed unusual cortical “cotton wool” plaques, immunoreactive for the beta-amyloid peptide but lacking congophilic cores. Patients and Methods: Twenty-two affected individuals (16 men and 6 women) were identified in four successive generations. All surviving five patients were examined and subjected to molecular genetic analysis. In addition, the neurologic records of nine deceased patients were evaluated. Electrophysiologic investigations were available in eight cases. CT or MRI of the head had been performed on 11 patients and PET was performed on three patients. Result:— The mean age at onset (±SD) was 50.9 ± 5.2 years (range 40 to 61 years). Memory impairment was present in all patients. Memory impairment appeared simultaneously with or was preceded by walking difficulty due to spasticity of the lower extremities (10/14). Impaired fine coordination of hands (9/14) and dysarthria (6/14) in some patients suggested cerebellar involvement. EEG showed intermittent generalized delta-theta activity. Head MRI showed temporal and hippocampal atrophy; PET showed bilateral temporo-parietal hypometabolism. Conclusion: Spastic paraparesis or brisk stretch reflexes of lower extremities or clumsiness of hands combined with dementia suggests this variant of AD.

Low density lipoprotein receptor‐related protein 5 (LRP5) mutations and osteoporosis, impaired glucose metabolism and hypercholesterolaemia

Objective  Mutations in the low‐density lipoprotein receptor‐related protein 5 gene (LRP5) underlie osteoporosis–pseudoglioma syndrome. Animal models implicate a role for LRP5 in lipid and glucose homeostasis. The objective was to evaluate metabolic consequences of LRP5 mutations in humans.

18q deletions : Clinical, molecular, and brain MRI findings of 14 individuals

We studied 14 individuals with partial deletions of the long arm of chromosome 18, including terminal and interstitial de novo and inherited deletions. Study participants were examined clinically and by brain MRI. The size of the deletion was determined by segregation analysis using microsatellite markers. We observed that the phenotype was highly variable, even in two families with three 1st degree relatives. Among the 14 individuals, general intelligence varied from normal to severe mental retardation. The more common features of 18q‐deletions (e.g., foot deformities, aural atresia, palatal abnormalities, dysmyelination, and nystagmus) were present in individuals lacking only the distal portion 18q22.3‐qtel. Interstitial deletions exerted very heterogeneous effects on phenotype. In individuals with distal 18q22.3‐q23 deletions, brain MRI was very distinctive with poor differentiation of gray and white matter on T2‐weighted images.

A new distal myopathy with mutation in anoctamin 5

We have been following clinically and with muscle MRI for the past 3-decades a Finnish family with two patients with distal muscular dystrophy. Previously we demonstrated the cellular defect in these patients to be defective membrane repair and more recently have identified the causative gene to be anoctamin 5 (ANO5). The disorder seen in these patients is characterized by onset in the third decade. First symptoms were burning sensation on the calves and later on calf tightness during running. Muscle weakness and wasting were asymmetric and early involving the calf muscles, later spread to the thigh muscles. Biceps brachi was later manifestation. Clinical course was slow. CK levels were high. Muscle biopsy showed dystrophic pattern and multifocal disruption of the sarcolemmal membrane but no subsarcolemmal vesicle accumulation nor active inflammation. We conclude that the disease seen in our cases is a new separate clinical, genetic and histopathologic entity to include within the classification of autosomal recessive distal muscular dystrophies.

Osteoporosis-pseudoglioma syndrome: clinical, morphological, and biochemical studies.

We report a sibship of a sister and brother with osteoporosis-pseudoglioma syndrome. Several other family members became blind or showed signs of bone involvement. There was considerable consanguinity in the pedigree. The proband was small in size and had prominent skeletal deformities and clinical muscle weakness. These features were not present in her brother, suggesting clinical variability. Mental function was normal in both. Bone histology showed osteopenia. Several biochemical events of procollagen biosynthesis were analysed in fibroblast cultures, but no significant abnormalities compared to control fibroblast cultures were detected.