Autosomal Dominant Locus Research Articles

Fine mapping and genetic heterogeneity in the pure form of autosomal dominant familial spastic paraplegia.

We evaluated seven families segregating pure, autosomal dominant familial spastic paraplegia (SPG) for linkage to four recently identified SPG loci on chromosomes 2q (1), 8q (2), 12q (3), and 19q (4). These families were previously shown to be unlinked to SPG loci on chromosomes 2p, 14q, and 15q. Two families demonstrated linkage to the new loci. One family (family 3) showed significant evidence for linkage to chromosome 12q, peaking at D12S1691 (maximum lod = 3.22). Haplotype analysis of family 3 did not identify any recombinants among affected individuals in the 12q candidate region. Family 5 yielded a peak lod score of 2.02 at marker D19S868 and excluded linkage to other known SPG loci. Haplotype analysis of family 5 revealed several cross-overs in affected individuals, thereby potentially narrowing the SPG12 candidate region to a 5-cM region between markers D19S868 and D19S220. Three of the families definitively excluded all four loci examined, providing evidence for further genetic heterogeneity of pure, autosomal dominant SPG. In conclusion, these data confirm the presence of SPG10 (chromosome 12), potentially reduce the minimum candidate region for SPG12 (chromosome 19q), and suggest there is at least one additional autosomal dominant SPG locus.

Silver syndrome is not linked to any of the previously established autosomal dominant hereditary spastic paraplegia loci.

The hereditary spastic paraplegias are a clinically variable and genetically heterogeneous group of disorders characterized by progressive and lower limb spasticity and weakness. Silver syndrome (SS) is a particularly disabling autosomal dominant form of the disease in which there is associated wasting of the hand muscles. In view of the fact that genes for hereditary spastic paraplegia can produce highly variable phenotypes, the eight known autosomal dominant loci were investigated for linkage to Silver syndrome. Genotyping of these loci in two large multigenerational families was incompatible with linkage to any of these regions, suggesting that an additional locus is responsible for this syndrome.

Análisis de segregación compleja de una familia numerosa con enfermedad cerebrovascular hereditaria en Antioquia (Colombia)

Among different kinds of cerebrovascular diseases, few of them are caused by genetic disturbances, such as CADASIL (caused by Notch3 mutations), CARASIL, mitochondrial encephalopathy, MELAS and dementia typed Binswanger. However, to describe these type of cerebrovascular diseases related with genetic mutations could permit to determinate the causes of both hereditary and sporadic cerebrovascular diseases and then lead solutions. To describe the genetic, environmental and cohort factors that determinate the presence of many affected people by a several cerebrovascular diseases in the pedigree of a large family from Antioquia (Colombia). We performed one pedigree (268 individuals), through singular recruit and then complex segregation analysis with POINTER program. The model that more close to data is autosomal dominant mayor locus without influence of environmental factors. Frequency of allele of susceptibility to develop stroke or subcortical vascular dementia was 0.0006. Mayor gene is over epistatic effects or interactions with other gene. Described an autosomal dominant hereditary model through complex segregation analysis in a pedigree of patients with hereditary cerebral vascular diseases characterized by recurrent strokes, early onset subcortical dementia, hearing loss, antecedent of migraine and MRI signal abnormalities, subcortical infarcts and leukoencephalopathy. In this family the parameter calculated, autosomal dominant model, and clinical feature strongly support the diagnostic of CADASIL, linkage analysis and sequentiation will be performed to determinate if mutant gene is Notch3.

Novel coding-region polymorphisms in mitochondrial seryl-tRNA synthetase (SARSM) and mitoribosomal protein S12 (RPMS12) genes in DFNA4 autosomal dominant deafness families.

Two genes for components of the mitochondrial translational apparatus, mitochondrial seryl-tRNA synthetase (SARSM) and mitoribosomal protein S12 (RPMS12) lie adjacent to one another on human chromosome 19, within the critical interval for the autosomal dominant deafness locus DFNA4. Both genes are plausible candidates for DFNA4, based on the fact that deafness mutations in mtDNA have been mapped both to tRNA-ser(UCN) and to the accuracy domain of the small subunit rRNA. We have sequenced the coding regions, proximal promoters, 5' and 3' UTR and splice junctional regions of both genes in two families with DFNA4-linked deafness and in controls. Novel polymorphisms 84425C>T, 83907A>G, 79485T>G, 79406C>T, 71755A>C and 68686C>G (numbered as in GenBank AC011455) were found in one or both families, but none is a plausible disease-causing mutation. Although regulatory mutations affecting either gene could still be involved in the phenotype, structural gene mutations affecting SARSM or RPMS12 can be excluded from consideration as the cause of DFNA4-linked deafness, at least in the families identified thus far.

Paroxysmal kinesigenic dyskinesia and infantile convulsions: clinical and linkage studies.

To clinically characterize affected individuals in families with paroxysmal kinesigenic dyskinesia (PKD), examine the association with infantile convulsions, and confirm linkage to a pericentromeric chromosome 16 locus. PKD is characterized by frequent, recurrent attacks of involuntary movement or posturing in response to sudden movement, stress, or excitement. Recently, an autosomal dominant PKD locus on chromosome 16 was identified. The authors studied 11 previously unreported families of diverse ethnic background with PKD with or without infantile convulsions and performed linkage analysis with markers spanning the chromosome 16 locus. Detailed clinical questionnaires and interviews were conducted with affected and unaffected family members. Clinical characterization and sampling of 95 individuals in 11 families revealed 44 individuals with paroxysmal dyskinesia, infantile convulsions, or both. Infantile convulsions were surprisingly common, occurring in 9 of 11 families. In only two individuals did generalized seizures occur in later childhood or adulthood. The authors defined a 26-cM region using linkage data in 11 families (maximum lod score 6.63 at theta = 0). Affected individuals in one family showed no evidence for a shared haplotype in this region, implying locus heterogeneity. Identification and characterization of the PKD/infantile convulsions gene will provide new insight into the pathophysiology of this disorder, which spans the phenotypic spectrum between epilepsy and movement disorder.

Evidence of genetic heterogeneity in autosomal recessive congenital fibrosis of the extraocular muscles

PURPOSE: Autosomal recessive congenital fibrosis of the extraocular muscles (CFEOM2) has been described in families from Saudi Arabia. Affected individuals have ptosis and exotropic ophthalmoplegia, and their disease has been mapped to chromosome 11q13. Here, we describe the phenotypic findings in a similarly affected Yemenite family and analyze the family for linkage to the CFEOM2 locus, as well as to the autosomal dominant CFEOM1 and CFEOM3 loci on chromosomes 12cen and 16q24, respectively. METHODS: The family was ascertained through two affected daughters. There are four unaffected siblings, and the parents are consanguineous. Each family member was examined, and linkage analysis was performed using markers from the CFEOM1, CFEOM2, and CFEOM3 loci. RESULTS: Both affected daughters have congenital bilateral ophthalmoplegia. The 15-month-old proband has restrictive exotropia. She fixates with either eye in abduction and with a compensatory head turn to the opposite side. Her 4-year-old sister has a small exotropia and severely limited eye movements. All other family members have normal ophthalmologic examinations. Genetic analysis excluded linkage of the family’s disease to the CFEOM2 and CFEOM3 loci. A lod score of 2.0 (the maximum possible, given the family size and structure), was obtained at the CFEOM1 locus, and the alleles reduced to homozygosity in both affected daughters and none of the other children. CONCLUSIONS: These data establish that there is genetic heterogeneity in autosomal recessive CFEOM and suggest that this second recessive locus may be allelic to the autosomal dominant CFEOM1 locus at 12cen.

Evidence for age-specific genetic relative risks in lung cancer.

Recent studies of familial aggregation suggest that family history of lung cancer among first-degree relatives is associated with increased risk for early-onset, but not late-onset, lung cancer. To assess whether this could be explained by variability in genetic relative risk across age, segregation analysis was performed on the Louisiana Lung Cancer Dataset. This data set consisted of 337 probands who died of lung cancer between 1976 and 1979 and their first-degree relatives. A variation of the Cox proportional hazards model was used that allowed estimation of age- and genotype-specific incidence rates, from which the authors obtained estimates of age-specific genetic relative risks. The best-fitting model included an autosomal dominant locus (allele frequency, 0.043), with carrier-to-noncarrier relative risks that exceeded 100 for ages less than 60 years and declined monotonically to 1.6 by age 80. The hypothesis of proportional genetic relative risk across age was rejected (p = 0.009). The estimated proportion of persons with lung cancer who carry the high-risk allele exceeds 90% for cases with onset at age 60 years or less and decreases to approximately 10% for cases with onset at age 80 years or older. These findings support previous evidence of a major susceptibility locus for lung cancer and suggest that linkage studies should preferentially recruit young lung cancer cases and their relatives.

Pigment Epithelium-Derived Factor Delays the Death of Photoreceptors in Mouse Models of Inherited Retinal Degenerations

Pigment epithelium-derived factor (PEDF) is a member of the serine protease inhibitor superfamily produced by retinal pigment epithelial cells in the developing and adult retina. In vitro, it induces neuronal differentiation of retinoblastoma cells and promotes survival of cerebellar granule neurons. The pedf gene is closely linked to an autosomal-dominant locus for retinitis pigmentosa, suggesting that PEDF could be a survival factor for photoreceptors. We have investigated this possibility by injecting PEDF into the eyes of homozygous retinal degeneration (rd) and retinal degeneration slow (rds) mice, two mutants displaying apoptotic photoreceptor loss. This procedure resulted in a transient delay of photoreceptor loss in the rd mouse and a reduction in apoptotic photoreceptor profiles in the rds mouse. We conclude that PEDF can act as a survival-promoting factor for photoreceptors in vivo and could potentially be useful for the treatment of photoreceptor diseases.

Autosomal dominant nonsyndromic hearing impairment.

Nearly all genes that have been localized for autosomal dominantly inherited hearing impairment are characterized by postlingual hearing loss that is progressive in nature. This auditory phenotype is in contrast to that of genes localized for autosomal recessive hearing impairment, which generally cause nonprogressive severe-to-profound or profound prelingual hearing loss. In most cases, extended pedigrees have been used to localize autosomal dominant deafness genes, To date, 22 autosomal dominant loci have been mapped, and 10 of these genes have been cloned. The functions of these deafness-causing genes are diverse and include transcription factors, extracellular matrix components, ion channels, cytoskeletal components, and unknown functions. Interesting findings include the unexpected expression pattern of some of these genes and the discovery that in some genes, allele variants can cause either isolated hearing loss or syndromic deafness. The greatest challenge for future research will be identifying additional deafness-causing genes and elucidating their function in the inner ear. Am. J. Med. Genet. (Semin. Med. Genet.) 89:167-174, 1999. @ 2000 Wiley-Liss, Inc.

Autosomal dominant nonsyndromic hearing impairment

Nearly all genes that have been localized for autosomal dominantly inherited hearing impairment are characterized by postlingual hearing loss that is progressive in nature. This auditory phenotype is in contrast to that of genes localized for autosomal recessive hearing impairment, which generally cause nonprogressive severe-to-profound or profound prelingual hearing loss. In most cases, extended pedigrees have been used to localize autosomal dominant deafness genes, To date, 22 autosomal dominant loci have been mapped, and 10 of these genes have been cloned. The functions of these deafness-causing genes are diverse and include transcription factors, extracellular matrix components, ion channels, cytoskeletal components, and unknown functions. Interesting findings include the unexpected expression pattern of some of these genes and the discovery that in some genes, allele variants can cause either isolated hearing loss or syndromic deafness. The greatest challenge for future research will be identifying additional deafness-causing genes and elucidating their function in the inner ear. Am. J. Med. Genet. (Semin. Med. Genet.) 89:167–174, 1999. @ 2000 Wiley-Liss, Inc.

Polyglutamine expansions: mechanisms of disease

The spinocerebellar ataxias (SCAs) are a complex group of often fatal neurodegenerative disorders. Five of the known autosomal dominant loci (SCA1–3, SCA6 and SCA7) are characterized by expanded CAG repeats that are translated into expanded polyglutamine tracts. It has previously been shown in SCA3 that polyglutamine expansion results in an altered, presumably misfolded, protein that forms intranuclear aggregates called nuclear inclusions (NIs). As NIs are ubiquinated, it might be that the ubiquitin–proteasome pathway is involved in the pathogenesis of this disorder.

Congenital Fibrosis of the Extraocular Muscles Type 2, an Inherited Exotropic Strabismus Fixus, Maps to Distal 11q13

The extraocular fibrosis syndromes are congenital ocular-motility disorders that arise from dysfunction of the oculomotor, trochlear, and abducens nerves and/or the muscles that they innervate. Each is marked by a specific form of restrictive paralytic ophthalmoplegia with or without ptosis. Individuals with the classic form of congenital fibrosis of the extraocular muscles (CFEOM1) are born with bilateral ptosis and a restrictive infraductive external ophthalmoplegia. We previously demonstrated that CFEOM1 is caused by an autosomal dominant locus on chromosome 12 and results from a developmental absence of the superior division of the oculomotor nerve. We now have mapped a variant of CFEOM, exotropic strabismus fixus ("CFEOM2"). Affected individuals are born with bilateral ptosis and restrictive ophthalmoplegia with the globes "frozen" in extreme abduction. This autosomal recessive disorder is present in members of three consanguineous Saudi Arabian families. Genetic analysis of 70 individuals (20 affected individuals) reveals linkage to markers on chromosome 11q13, with a combined LOD score of 12.3 at the single nonrecombinant marker, D11S1314. The 2.5-cM CFEOM2 critical region is flanked by D11S4196/D11S4162 and D11S4184/1369. Two of the three families share a common disease-associated haplotype, suggesting a founder effect for CFEOM2. We hypothesize that CFEOM2 results from an analogous developmental defect to CFEOM1, one that affects both the superior and inferior divisions of the oculomotor nerve and their corresponding alpha motoneurons and extraocular muscles.

Connexin-26 mutations in sporadic non-syndromal sensorineural deafness

Congenital or childhood-onset sensorineural deafness affects about one in 1000 children and is especially important since it impedes oral language acquisition. Most cases (about 70%) are non-syndromal—ie, they occur in the absence of associated features. Although non-syndromal sensorineural deafness usually occurs sporadically, a genetic cause is responsible in up to 60% of cases, most (about 75%) of which are inherited in an autosomal recessive manner. Clinical and audiological features such as age of onset and severity do not usually allow reliable discrimination between acquired and genetic causes when providing estimates of recurrence risk for genetic counselling in an individual family. Recurrence risks for subsequent offspring are therefore based on empirical data. Non-syndromal sensorineural deafness is genetically heterogeneous with, to date, 20 autosomal recessive and 13 autosomal dominant loci mapped. 1 Van Camp G Willems PJ Smith RJH Nonsyndromic hearing impairment: unparalleled heterogeneity. Am J Hum Genet. 1997; 60: 758-764 PubMed Google Scholar Recently, mutations in the connexin-26 gene (Cx26) have been shown to result in autosomal recessive (DFNB1) and dominant (DFNA3) non-syndromal sensorineural deafness. 2 Kelsell DP Dunlop J Stevens HP et al. Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature. 1997; 387: 80-83 Crossref PubMed Scopus (1218) Google Scholar In addition, a single mutation in the connexin-26 gene, 30delG, accounts for most (about 70%) of Cx26 mutant alleles in families that originate from the UK, France, Italy, Spain, Tunisia, Lebanon, Australia, and New Zealand. 3 Denoyelle F Weil D Maw MA et al. Prelingual deafness: high prevalence of a 30delG mutation in the connexin 26 gene. Hum Mol Genet. 1997; 6: 2173-2177 Crossref PubMed Scopus (551) Google Scholar , 4 Zelante L Gasparini P Estivill X et al. Connexin 26 mutations associated with the most common form of non-syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans. Hum Mol Genet. 1997; 6: 1605-1609 Crossref PubMed Scopus (546) Google Scholar To determine the prevalence of Cx26 mutations in sporadic non-syndromal sensorineural deafness, we studied a cohort of 68 non-consanguineous UK and Belgian singletons. Connexin 26 gene mutation and autosomal recessive deafnessGenetic deafness is common, with an estimated prevalence of 1 per 2000 births. Writing in 1853, before the laws of mendelian inheritance had even been promulgated, Sir William Wilde recognised that the pattern of transmission of deafness varied from family to family, and he clearly identified autosomal dominant, autosomal recessive, and X-linked forms.1 Latterly, attempts by researchers to identify homogeneous families on the basis of associated clinical features have led to the recognition of the clinically distinct syndromic forms of deafness, which have formed the basis of much recent progress. Full-Text PDF Connexin-26 mutations in sporadic and inherited sensorineural deafnessMutations in the GJB2 gene are a major cause of inherited and apparently sporadic congenital deafness. Mutation 35delG is the most common mutation for sensorineural deafness. Identification of 35delG and other mutations in the GJB2 gene should facilitate diagnosis and counselling for the most common genetic form of deafness. Full-Text PDF

Genetic testing for Alzheimer disease. Practical and ethical issues.

The dissection of the heterogeneous genetics of the Alzheimer diseases (ADs) is currently more advanced than in any other common disease. Not only are 3 uncommon autosomal dominant mutation loci identified, but universally inherited susceptibility polymorphisms associated with risk and age of onset distributions for familial and "sporadic" AD are also confirmed. The utility of testing for mutations of the amyloid precursor protein and the presenilin 1 and presenilin 2 genes conforms to strategies in common use for rare mutations. The selection of patients with very early-onset AD, especially those with family histories of the disease, will increase the possibility of diagnosis. All testing should be performed using recommended counseling procedures. Apolipoprotein E (ApoE) susceptibility polymorphisms are genetic risk factors but do not allow prediction of the age of onset of AD for cognitively normal individuals. Recent large, collaborative studies have found that when ApoE genotyping is used sequentially in diagnosis following criteria-based evaluations, the specificity of early diagnosis is significantly increased. For patients clinically diagnosed with AD who carried an ApoE epsilon 4 allele, the positive predictive value was 94% and 97% in 2 multicenter collaborative series. The utility of ApoE genotyping is reviewed and recommendations for early use in diagnosis are explained. There are ethical, social, actuarial, and legal problems currently associated with genetic testing and these concerns are also discussed.

Mutilating neuropathic ulcerations in a chromosome 3q13-q22 linked Charcot-Marie-Tooth disease type 2B family.

BACKGROUND: Charcot-Marie-Tooth disease type 2 (CMT2) or hereditary motor and sensory neuropathy type II (HMSN II) is an inherited axonal neuropathy of the peripheral nervous system. Three autosomal dominant CMT2...

Retinopathy induced in mice by targeted disruption of the rhodopsin gene.

Retinitis pigmentosa (RP) represents the most common mendelian degenerative retinopathy of man, involving death of rod photoreceptors, cone cell degeneration, retinal vessel attenuation and pigmentary deposits. The patient experiences night blindness, usually followed by progressive loss of visual field. Genetic linkage between an autosomal dominant RP locus and rhodopsin, the photoreactive pigment of the rod cells, led to the identification of mutations within the rhodopsin gene in both dominant and recessive forms of RP. To better understand the functional and structural role of rhodopsin in the normal retina and in the pathogenesis of retinal disease, we generated mice carrying a targeted disruption of the rhodopsin gene. Rho-/- mice do not elaborate rod outer segments, losing their photoreceptors over 3 months. There is no rod ERG response in 8-week-old animals. Rho+/- animals retain the majority of their photoreceptors although the inner and outer segments of these cells display some structural disorganization, the outer segments becoming shorter in older mice. These animals should provide a useful genetic background on which to express other mutant opsin transgenes, as well as a model to assess the therapeutic potential of re-introducing functional rhodopsin genes into degenerating retinal tissues.

A Gene Similar to PKD1 Maps to Chromosome 4q22: A Candidate Gene for PKD2

We report a partial cDNA sequence that encodes a protein, dubbed “polycystwin,” with 21% identity and 46% similarity to amino acids 3688–4109 of the carboxyl terminus of polycystin, the gene product of the autosomal dominant polycystic kidney disease locus located on chromosome 16 at band p13 (PKD1). Northern analysis demonstrates that the R48321 gene is expressed in all tissues examined, including both adult and fetal kidneys. Finally,in situhybridization studies localize this novel gene to 4q22, where PKD2, the second most common locus for ADPKD, is known to map. Therefore, R48321 is an excellent candidate gene for PKD2.

An autosomal dominant locus, Nka, mapping to the Ly-49 region of a rat natural killer (NK) gene complex, controls NK cell lysis of allogeneic lymphocytes.

Natural Killer (NK) cells can recognize and kill MHC-incompatible normal bone marrow-derived cells. Presently characterized MHC-binding receptors on NK cells, including the Ly-49 family in the mouse, transmit inhibitory signals upon binding to cognate class I MHC ligands. Here we study in vivo NK-mediated lysis of normal allogeneic lymphocytes in crosses between alloreactivity-competent PVG rats and alloreactivity-deficient DA rats. NK cells from both strains are able to lyse standard tumor targets. We identify an autosomal dominant locus, Nka, that controls NK-mediated alloreactivity. Individuals carrying the dominant PVG allele in single dose were fully competent in eliminating allogeneic target cells, suggesting that Nka encodes or regulates a gene product inducing or activating alloreactivity. By linkage analysis and pulsed field gel electrophoresis, a natural killer gene complex (NKC) on rat chromosome 4 is described that contains the rat NKR-P1 and Ly-49 multigene families plus a rat NKG2D homologue. Nka maps within the NKC, together with the most telomeric Ly-49 family members, but separate from NKG2D and the NKR-P1 family. The Nka-encoded response, moreover, correlates with the expression of transcripts for Ly-49 receptors in NK cell populations, as Northern blot analysis demonstrated low expression of Ly-49 genes in DA NK cells, in contrast to high expression in alloreactivity-competent PVG, (DA X PVG)F1, and PVG.1AVI NK cells. The low Ly-49 expression in DA is not induced by MHC haplotype, as demonstrated by high expression of Ly-49 in the DA MHC-congenic PVG.1AVI strain. Finally, we have cloned and characterized the first four members of the rat Ly-49 gene family. Their cytoplasmic domains demonstrate substantial heterogeneity, consistent with the hypothesis that different Ly-49 family members may subserve different signaling functions.

Exclusion of the involvement of all known retinitis pigmentosa loci in the disease present in a family of Irish origin provides evidence for a sixth autosomal dominant locus (RP8).

Retinitis Pigmentosa (RP) is the most prevalent degenerative retinal disease of mendelian origin, currently affecting approximately 1.5 million people worldwide. To date it has been established that a minimum of five different genes maybe involved in the pathogenesis of autosomal dominant forms of RP (adRP). The genes encoding two retinal specific proteins, rhodopsin and peripherin/RDS, have been implicated in causing adRP due to the observation of many different mutations in these genes in patients suffering from RP. The three remaining adRP genes have been mapped to specific regions of human chromosomes but as yet are uncharacterized. We have investigated if there is evidence for the presence of another locus in the genome which when mutated causes adRP. We have utilised polymorphic genetic markers which have previously been mapped to each of the regions known to harbour adRP genes, to test for the exclusion or linkage of the disease gene segregating in a pedigree of Irish origin and find no evidence for linkage. Hence we provide definitive evidence for the involvement of yet another locus. The implications of high levels of genetic heterogeneity inherent in adRP are discussed in relation to diagnosis, prognosis and future therapies.

The Genetics of Obsessive Compulsive Disorder and Gilles De La Tourette’s Syndrome

This article reviews the evidence that obsessive compulsive disorder (OCD) and Gilles de la Tourette's syndrome (GTS) are both familial and genetic. Studies are summarized that suggest that (1) some forms of OCD are related to GTS, (2) some forms of OCD are familial and may not be related to GTS, and (3) the patterns of inheritance of GTS and OCD within the same families are consistent with the transmission of an autosomal dominant genetic locus.