From gene to disease; the PABN1 gene and oculopharyngeal muscular dystrophy

Oculopharyngeal muscular dystrophy is a rare disease, presenting with bilateral ptosis and dysphagia, followed by slow progressive muscle weakness. The pathological hallmark of the disease is the presence of intranuclear inclusions in muscle cells. Inheritance is autosomal dominant in almost all cases. The mutation responsible is a short guanine-cytosine-guanine (GCG) expansion in the 'poly adenylate binding nuclear I protein' (PABN1) gene. This expansion is stable in subsequent generations and is translated into a polyalanine tract. The aberrant protein is found within the intranuclear inclusions and interferes with normal mRNA function.     

From gene to disease; the dystrophin gene involved in Duchenne and Becker muscular dystrophy

Duchenne and Becker muscular dystrophy (DMD and BMD) are progressive disorders, which almost exclusively affect males. DMD is the more severe type with an onset at 2-3 years of age. Patients become wheelchair-bound before the age of 13 and often die due to cardiac arrest or respiratory insufficiency. BMD, a more varying phenotype which may overlap with limb girdle muscular dystrophy (LGMD), has a less severe muscle weakness which starts later than in DMD patients. DMD carriers may show some muscle weakness. The dystrophin gene (2.4 Mb), known to be involved in DMD/BMD, codes for a 427 kilodalton muscle-specific protein named dystrophin as well as several tissue-specific isoforms. Dystrophin, as part of a membrane-bound complex of proteins, connects the cytoskeleton of the muscle cell to the extracellular matrix. Since 1985, when highly reliable carrier detection and prenatal diagnosis at the DNA level became possible, over 250 prenatal tests have been performed. Molecular genetic analysis, highlighted a phenomenon called germinal mosaicism, which explains the recurrence of de novo mutations and led to the discovery of the so-called reading-frame rule, which helps to discriminate between DMD and BMD. Fifteen years after the discovery of the dystrophin gene, mutations can be detected in 95% of the patients, while the remaining 5% are still hiding within this very large gene.     

A case of Creutzfeldt-Jakob disease related to familial retinitis pigmentosa patients

Similarities between serological alterations and retinal degeneration occurring in natural and experimental CJD and in some forms of human retinal degeneration have recently been reported. In the present paper a family from an areal focal accumulation of CJD in Central Slovakia with 1 histopathologically verified case of Creutzfeldt-Jakob disease and 2 case of retinitis pigmentosa is described. Neuropathological and epidemiological data obtained in investigated patients are discussed from the point of view of a possible relationship between the slow virus infections caused by unconventional agents and degenerative disease affecting the ocular system.     

From gene to disease: introduction

The knowledge of the molecular basis of many diseases is expanding rapidly. Consequently, molecular pathophysiology is becoming an integral part of all medical specialisms. In the evaluation of the relation between genes and diseases many aspects have to be considered: clinical manifestations of disease, gene structure, structure and function of the molecule encoded by the gene and molecular epidemiology in order to dissect the impact of molecular alterations in the population. In the series 'From gene to disease' these clinical, molecular and epidemiological aspects will be described for a number of diseases.     

From gene to disease: cystinosis

Cystinosis is an autosomal recessive disorder caused by an impaired transport of cystine out of lysosomes. The most severe infantile form of cystinosis starts with Fanconi syndrome at the age of 3-6 months. Untreated patients develop renal failure before the age of 10. The cystinosis gene (CTNS) maps to chromosome 17p13, spans 23 kb and is composed of 12 exons. CTNS encodes a 367 amino acid protein, cystinosin, which is a H(+)-driven lysosomal cystine transporter. It is enigmatic how lysosomal cystine accumulation induces the clinical symptoms. ATP depletion was demonstrated in an experimental model consisting of loading lysosomes with cystine dimethylester. The amino-thiol cysteamine depletes lysosomal cystine content by a disulfide-exchange reaction with cystine. Therapy with cysteamine should be administered as early as possible and continued after a renal transplantation as the extra renal damage still progresses. Improved life expectancy of cystinotic patients requires the attention of internists with a special interest for this rare disorder.     

From gene to disease; from polycystines to polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease that results in multiple cysts in the kidneys and other organs and leads to endstage renal failure relatively late in life. The disease results from mutations in one of two independently segregating genes that under normal conditions produce polycystines. Polycystines are membrane proteins that form a complex involved in signal transduction in epithelial cells. Genetic heterogeneity explains in part the various ADPKD phenotypes.     

From gene to disease; from homocysteine to hyperhomocysteinemia

Homocysteine is a sulfhydryl containing amino acid which is produced as an intermediate product in the metabolism of the essential amino acid methionine. Apart from environmental factors such as the intake of folate and other B vitamins, the level of homocysteine in the blood is determined by the genetically based activities of several enzymes involved in the methionine or folate cycle. The well-known congenital defect homocystinuria is due to homozygosity for mutated cystathionine beta synthase. It is characterized by severe hyperhomocysteinemia, which leads to arterial and venous disease at a very young age. Mild to moderate hyperhomocysteinemia, due to either heterozygosity for severe mutations in the genes of enzymes involved or based upon homozygosity for more mild mutations, has also been recognized as a risk factor for vascular disease in the last decade. However, ongoing clinical intervention studies still need to demonstrate a casual role of mildly increased homocysteine levels in vascular disease.     

From gene to disease: Fanconi anemia

Fanconi anaemia (FA) is an autosomal recessive hereditary disease featuring diverse clinical symptoms and a cellular hypersensitivity to cross-linking agents. FA patients suffer from developmental abnormalities, progressive anaemia and an increased risk of developing cancer. FA is associated with mutations in one of the group of seven FA genes identified to date. FA genes encode proteins that control a molecular pathway which ensures an adequate defence against certain types of genomic instability and the associated risk of developing cancer. DNA diagnostics is possible.     

From gene to disease; from p16 to melanoma

Approximately 10% of human cutaneous melanoma cases occur in families with the familial atypical multiple mole melanoma (FAMMM) syndrome, which is characterised by the familial occurrence of melanomas and atypical precursor naevi. A melanoma-associated gene has been mapped to 9p2l, encoding for the tumour suppressor gene CDKN2A. Worldwide, germline mutations in melanoma kindreds implicate this cell cycle regulator (p16) as a susceptibility gene for malignant melanoma. Most FAMMM families registered at the Leiden Pigmented Lesions Clinic share the same CDKN2A inactivating deletion (P16-Leiden). Presymptomatic DNA diagnosis will now be available for P16-Leiden positive FAMMM family members at the Leiden University Medical Centre.     

From gene to disease: deafness and connexin 26

Deafness is genetically heterogeneous, yet it is estimated that approximately half of the heritable cases of autosomal recessive deafness are caused by mutations in the gene coding for connexin 26. Connexin 26 is thought to have an essential role in the transport of potassium ions back to the endolymph of the inner ear after sound stimulation.     

From gene to disease: amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a progressive neurological disorder. It is characterised by selective motor-neuron degeneration in the cortex, brainstem, and spinal cord. Consequently, patients suffer from muscle weakness and usually die within 3-5 years after diagnosis from respiratory insufficiency. About 5-10% of the patients have a family history of ALS, the remaining are classified as sporadic ALS. There is only limited information about genetic susceptibility factors in sporadic ALS. Some patients with familial ALS have mutations in the gene encoding for copper/zinc superoxide dismutase, a protein involved in scavenging superoxide radicals. This results in a toxic gain of function. Mutations in the gene coding for alsin, ALS2, have been shown to be responsible for an autosomal recessive form of juvenile ALS.     

From gene to disease; Gaucher disease

Gaucher disease is an autosomal recessive inherited lysosomal storage disorder due to mutations in the glucocerebrosidase gene located on chromosome 1q21. Hepatosplenomegaly and bone disease due to massive accumulation of undegraded glucocerebroside in macrophages found in the liver, spleen and bone marrow dominate the clinical picture in type 1 disease. In rare instances (type 2 and 3 disease) the central nervous system is involved. Phenotype-genotype correlations are poor. Diagnosis is possible by enzyme assay at clinical genetic centres in the Netherlands. The availability of effective therapies emphasizes the need for early recognition of the disease.     

From gene to disease; from SDHD,a defect in the respiratory chain,to paragangliomas and pheochromocytomas

Hereditary paragangliomas are rare benign tumours arising from neuroectodermal tissue in the head and neck region. In families with paraganglioma, occasionally adrenal and extra-adrenal pheochromocytomas are found. Paragangliomas, adrenal and extra-adrenal pheochromocytomas may be caused by mutations in the SDHB, SDHC and SDHD genes encoding different subunits of mitochondrial respiratory chain complex II. Most paraganglioma cases in the Netherlands are caused by SDHD mutations. Presymptomatic DNA diagnosis is available for families with paragangliomas caused by SDHD mutations.     

From gene to disease; HD gene and Huntington disease]

Huntington's disease (HD) is a late onset, incurable, autosomal dominantly-inherited, progressive neuropsychiatric disease, characterised by chorea, changes in personality, mood and behaviour, and dementia. Huntington's disease is a clinical diagnosis. The advent of DNA diagnosis has made predictive, prenatal and preimplantation testing possible for at-risk persons or asymptomatic carriers. The prevalence is estimated to be 3-10/100,000 among individuals of European descent; HD is less common in other ethnic groups. Huntington's disease is caused by an expanded trinucleotide CAG repeat in the HD gene on chromosome 4. The gene encodes for the protein huntingtin, with an as yet unknown function. The mutated huntingtin has an elongated stretch of glutamines which leads to a gain of function such as overactivity, excitotoxicity, or to interactions with other proteins.     

From gene to disease; from CACNA1A to migraine

Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura. FHM is associated in half the families with mutations in the CACNA1A gene on chromosome 19P13, encoding the alpha-1A subunit of brain-specific P/Q-type calcium channels. P/Q-type calcium channels are important in neurotransmitter release. The first functional studies indicate that mutations causing FHM result in a gain or loss of function of P/Q-type calcium channels. Affected sib-pair analysis in families with migraine with and without aura indicates involvement of the CACNA1A gene in these more frequent types of migraine.     

From gene to disease: adrenogenital syndrome and the CYP21A2 gene

Congenital adrenal hyperplasia (CAH) is a disorder of adrenal steroid synthesis. In more than 90% of cases CAH is caused by CYP21 (21-hydroxylase) deficiency leading to impaired cortisol and aldosterone synthesis and an increase in ACTH secretion. This then leads to stimulation of the adrenal gland and overproduction of androgens with virilisation of female external genitalia. The CYP21 enzyme consists of 495 amino acids and is encoded by the CYP21A2 gene located on chromosome 6p21.3 close to a 98% homologous pseudogene (CYP21p). The pseudogene contains several inactivating mutations that may be transferred to the active CYP21A2 gene by gene conversion (more than 60% of the affected alleles) or gene deletion (30% of the affected alleles). The severity of the disease depends on the degree of CYP21 deficiency. The diagnosis can be made by measuring levels of 17-hydroxyprogesterone and androstenedione in serum.