A locus for autosomal recessive hypodontia with associated dental anomalies maps to chromosome 16q12.1

Lumbosacral defects on 20 patients were covered with a perforator-based flap. Cutaneous perforators derived from the 9th and 10th intercostal arteries, the 4th lumbar artery, and multiple gluteal perforators that penetrate the gluteus maximus muscle were used as vascular pedicles. Minor complications occurred in five cases. Using this method, minimal morbidity of the donor site is expected because the gluteus maximus need not be sacrificed. Accordingly, perforator-based flaps are especially indicated for ambulatory patients, but for paraplegic patients as well. Even in the event of recurrence, another perforator-based or musculocutaneous flap can be elevated from the ipsilateral side because of the presence of multiple perforators in the lumbosacral and gluteal regions.     

A first locus for isolated autosomal recessive optic atrophy (ROA1) maps to chromosome 8q

In contrast to the frequent dominant optic atrophies (DOAs) in which the neuropathy is usually an isolated event, isolated recessive optic atrophies (ROAs) are very uncommon and have been described as severe congenital or early infantile conditions. To date, two loci for isolated DOA have been mapped, of which one was ascribed to mutations in the OPA1 gene. Conversely, no isolated autosomal ROA locus had previously been localised. Here, we report a large multiplex consanguineous family of French origin affected with an early onset but slowly progressive form of isolated OA. A genome-wide search for homozygosity allowed the localisation of the disease-causing gene to chromosome 8q21-q22 (Zmax of 3.41 at theta=0 for D8S270), in a 12 Mb interval flanked by markers D8S1702 and D8S1794. This localisation excludes allelism of the disease with both isolated DOAs, on one hand, or all known syndromic forms of ROA, on the other hand, supporting the mapping of a first gene for isolated autosomal ROA (ROA1) on the long arm of chromosome 8.     

Gene locus for autosomal recessive distal myopathy with rimmed vacuoles maps to chromosome 9

Distal myopathy with rimmed vacuoles is an autosomal recessive muscular disorder, characterized clinically by weakness of the distal muscles in the lower limbs in early adulthood. Recently, the gene locus for familial vacuolar myopathy with autosomal recessive inheritance (hereditary inclusion body myopathy) was mapped to chromosome 9 by genome-wide linkage analysis of nine Persian-Jewish families. Since both disease conditions share similar clinical, genetic, and histopathological features, we analyzed seven families with distal myopathy with rimmed vacuoles using ten microsatellite markers within the region of the hereditary inclusion body myopathy locus. Significantly high cumulative pairwise lod scores were obtained with three markers: D9S248 (Z(max) = 5.90 at theta = 0), D9S43 (Z(max) = 5.25 at theta = 0), and D9S50 (Z(max) = 4.23 at theta = 0). Detection of obligate recombination events as well as multipoint linkage analysis revealed that the most likely location of the distal myopathy with rimmed vacuoles gene is in a 23.3-cM interval defined by D9S319 and D9S276 on chromosome 9. The results raise the possibility that distal myopathy with rimmed vacuoles and hereditary inclusion body myopathy in Persian Jews are allelic diseases.     

A gene for autosomal recessive symmetrical spastic cerebral palsy maps to chromosome 2q24-25

Cerebral palsy has an incidence of approximately 1/500 births, although this varies between different ethnic groups. Genetic forms of the disease account for approximately 1%-2% of cases in most countries but contribute a larger proportion in populations with extensive inbreeding. We have clinically characterized consanguineous families with multiple children affected by symmetrical spastic cerebral palsy, to locate recessive genes responsible for this condition. The eight families studied were identified from databases of patients in different regions of the United Kingdom. After ascertainment and clinical assessment, we performed a genomewide search for linkage, using 290 polymorphic DNA markers. In three families, a region of homozygosity at chromosome 2q24-q25 was identified between the markers D2S124 and D2S148. The largest family gave a maximum LOD score of 3.0, by multipoint analysis (HOMOZ). The maximum combined multipoint LOD score for the three families was 5.75. The minimum region of homozygosity is approximately 5 cM between the markers D2S124 and D2S2284. We have shown that a proportion of autosomal recessive symmetrical spastic cerebral palsy maps to chromosome 2q24-25. The identification of genes involved in the etiology of cerebral palsy may lead to improved management of this clinically intractable condition.     

A gene for autosomal recessive limb-girdle muscular dystrophy maps to chromosome 2p

The limb-girdle muscular dystrophies are a clinically and genetically heterogeneous group of disorders. We have studied two large inbred families of different ethnic origin and excluded linkage to LGMD2 on chromosome 15q and SCARMD on chromosome 13. Proceeding to a genomic linkage search, we have now identified linkage to markers D2S134 and D2S136 on chromosome 2p (maximum lod score 3.57 at zero recombination). The phenotype in the two families was similar, with onset in the pelvic girdle musculature in the late teens and usually relatively slow progression. This work identifies a second locus for autosomal recessive limb-girdle muscular dystrophy.     

A second locus for familial high myopia maps to chromosome 12q

Myopia, or nearsightedness, is the most common eye disorder worldwide. "Pathologic" high myopia, or myopia of <=-6.00 diopters, predisposes individuals to retinal detachment, macular degeneration, cataract, or glaucoma. A locus for autosomal dominant pathologic high myopia has been mapped to 18p11.31. We now report significant linkage of high myopia to a second locus at the 12q21-23 region in a large German/Italian family. The family had no clinical evidence of connective-tissue abnormalities or glaucoma. The average age at diagnosis of myopia was 5.9 years. The average spherical-component refractive error for the affected individuals was -9.47 diopters. Markers flanking or intragenic to the genes for the 18p locus, Stickler syndromes type I and II (12q13.1-q13.3 and 6p21.3), Marfan syndrome (15q21.1), and juvenile glaucoma (chromosome 1q21-q31) showed no linkage to the myopia in this family. The maximum LOD score with two-point linkage analysis in this pedigree was 3.85 at a recombination fraction of .0010, for markers D12S1706 and D12S327. Recombination events identified markers D12S1684 and D12S1605 as flanking markers that define a 30.1-cM interval on chromosome 12q21-23, for the second myopia gene. These results confirm genetic heterogeneity of myopia. The identification of this gene may provide insight into the pathophysiology of myopia and eye development.     

A new locus for hemiplegic migraine maps to chromosome 1q31

A single familial hemiplegic migraine locus has been previously mapped to 19p13.1 and associated with mutations in a calcium channel gene (CACNL1A4). We describe a new 39-member four-generation family from Wyoming of German-Native American descent with autosomal dominant familial hemiplegic migraine that is not linked to the chromosome 19p locus. Affected individuals showed a stereotypic pattern of migrainous headache associated with hemisensory and hemiparetic attacks, without other headache types. Eighty-three percent reported minor head trauma as a trigger for individual attacks. Seventy-two percent reported other typical migraine triggers for the attacks. Attack frequency decreased with age and the overall course was benign. Genetic linkage studies of this family found strong evidence for the disease gene in this family being located at chromosome 1q31. Multipoint analysis showed lod scores > 3 in a 44-cm region flanked by D1S158 and D1S2781, using 80% penetrance and a phenocopy rate of 1/50. Haplotype and multipoint analysis, including flanking markers, suggested incomplete penetrance and variable expressivity of the disease. A single affected patient who reports atypical symptoms including daily headaches likely represents a phenocopy. This new locus for hemiplegic migraine suggests that mutations of additional calcium channels in the region may cause the disease.     

The porcine TTR locus maps to chromosome 6q

The sequence of a cDNA clone encoding porcine transthyretin (prealbumin) was used to develop polymorphic markers for the TTR locus. The single-strand conformation polymorphism (SSCP) detected is caused by a silent A/T mutation in the penultimate coding codon and can also be revealed as a SacI restriction fragment length polymorphism (RFLP). The TTR locus was mapped to chromosome 6q by segregation and linkage analysis with these polymorphisms. This assignment confirms the predictions of homology between human chromosome 18 and pig chromosome 6q2.5-q2.6.     

A disease locus for familial hypertrophic cardiomyopathy maps to chromosome 1q3

Familial hypertrophic cardiomyopathy (FHC) is caused by missense mutations in the beta cardiac myosin heavy chain (MHC) gene in less than half of affected individuals. To identify the location of another gene involved in this disorder, a large family with FHC not linked to the beta MHC gene was studied. Linkage was detected between the disease in this family and a locus on chromosome 1q3 (maximum multipoint lod score = 8.47). Analyses in other families with FHC not linked to the beta MHC gene, revealed linkage to the chromosome 1 locus in two and excluded linkage in six. Thus mutations in at least three genetic loci can cause FHC. Three sarcomeric contractile proteins--troponin I, tropomyosin and actin--are strong candidate FHC genes at the chromosome 1 locus.     

A novel locus for autosomal dominant nonsyndromic hearing loss, DFNA13, maps to chromosome 6p

Nonsyndromic hearing loss (NSHL) is the most common type of hearing impairment in the elderly. Environmental and hereditary factors play an etiologic role, although the relative contribution of each is unknown. To date, 39 NSHL genes have been localized. Twelve produce autosomal dominant hearing loss, most frequently postlingual in onset and progressive in nature. We have ascertained a large, multigenerational family in which a gene for autosomal dominant NSHL is segregating. Affected individuals experience progressive hearing loss beginning in the 2d-4th decades, eventually making the use of amplification mandatory. A novel locus, DFNA13, was identified on chromosome 6p; the disease gene maps to a 4-cM interval flanked by D6S1663 and D6S1691, with a maximum two-point LOD score of 6.409 at D6S299.     

Novel locus for autosomal dominant hereditary spastic paraplegia, on chromosome 8q

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of disorders characterized by insidiously progressive spastic weakness in the legs. Genetic loci for autosomal dominant HSP exist on chromosomes 2p, 14q, and 15q. These loci are excluded in 45% of autosomal dominant HSP kindreds, indicating the presence of additional loci for autosomal dominant HSP. We analyzed a Caucasian kindred with autosomal dominant HSP and identified tight linkage between the disorder and microsatellite markers on chromosome 8q (maximum two-point LOD score 5.51 at recombination fraction 0). Our results clearly establish the existence of a locus for autosomal dominant HSP on chromosome 8q23-24. Currently this locus spans 6.2 cM between D8S1804 and D8S1774 and includes several potential candidate genes. Identifying this novel HSP locus on chromosome 8q23-24 will facilitate discovery of this HSP gene, improve genetic counseling for families with linkage to this locus, and extend our ability to correlate clinical features with different HSP loci.     

Mapping of a congenital microcoria locus to 13q31-q32

The growth and timing of female puberty in a seasonally breeding marsupial, the tammar wallaby, was examined in wild and captive animals. Puberty, defined as the time of first estrus and ovulation, can occur at any time of the year. Sixty percent of young wild females went through puberty in late October-November, 3 mo before the normal adult mating season in late January-February, but puberty was delayed in captive animals kept with a low ratio of males to females. During initial cycles, 19% of these captive animals were infertile as judged by failure to conceive. In the wild, puberty occurred well before the animals were fully grown (body weight 2.0+/-0.3 kg [mean+/-SD], n=23; adult females, 4.7+/-0.6 kg; n=34). Only 3% of animals with a body weight below 1.5 kg had ovulated. Thus, attainment of a minimum body weight was a key prerequisite associated with puberty. Progesterone concentrations in the peripheral plasma of prepubertal females were not significantly different from those of adult females during the nonbreeding season (prepubertal, 142+/-121 pg/ml, n=34; adult, 194+/-105 pg/ml, n=32, p > 0.05). However, there was a significant increase in progesterone (322+/-242 pg/ml, n=32, p < 0.05) in the postpubertal females (ovulating but still < 3.5 kg body weight) even though the corpus luteum was quiescent after its formation. There was no increase in plasma progesterone before the first estrus. These data confirm that estrus does not require a change in the progesterone:estradiol ratio, and that a "silent" ovulation does not precede the first estrus in this species, so that the onset of puberty coincides with the first behavioral estrus and ovulation, when the animals have reached a body weight of 2 kg. Although adult female tammars are strict seasonal breeders, with 6 mo of seasonal quiescence from the winter to the summer solstice, young females can go through puberty at any time of the year. The unique feature of the female tammar wallaby is that it does not become a seasonally breeding mammal until after puberty, when it has acquired a corpus luteum.     

A gene for autosomal dominant hypohidrotic ectodermal dysplasia (EDA3) maps to chromosome 2q11-q13

Autosomal dominant hypohidrotic ectodermal dysplasia (ADHED) is a disorder characterized by fine, slow-growing scalp and body hair, sparse eyebrows and eyelashes, decreased sweating, hypodontia, and nail anomalies. By genetic linkage analysis of a large ADHED kindred, we have mapped a gene for ADHED (EDA3) to the proximal long arm of chromosome 2 (q11-q13). Obligate recombinations localize EDA3 to an approximately 9-cM interval between D2S1321 and D2S308, with no apparent recombinations with markers D2S1343, D2S436, D2S293, D2S1894, D2S1784, D2S1890, D2S274, and CHLC.GAAT11C03.     

A gene for familial juvenile polyposis maps to chromosome 18q21.1

Bacillus subtilis cells respond almost immediately to different stress conditions by increasing the production of general stress proteins (GSPs). The genes encoding the majority of the GSPs that are induced by heat, ethanol, salt stress or by starvation for glucose, oxygen or phosphate belong to the sigmaB-dependent general stress regulon. Despite a good understanding of the complex regulation of the activity of sigmaB and knowledge of a very large number of general stress genes controlled by sigmaB, first insights into the physiological role of this nonspecific stress response have been obtained only very recently. To explore the physiological role of this reguIon, we and others identified sigmaB-dependent general stress genes and compared the stress tolerance of wild-type cells with mutants lacking sigmaB or general stress proteins. The proteins encoded by sigmaB-dependent general stress genes can be divided into at least five functional groups that most probably provide growth-restricted B. subtilis cells with a multiple stress resistance in anticipation of future stress. In particular, sigB mutants are impaired in non-specific resistance to oxidative stress, which requires the sigmaB-dependent dps gene encoding a DNA-protecting protein. Protection against oxidative damage of membranes, proteins or DNA could be the most essential component of sigmaB mediated general stress resistance in growth-arrested aerobic gram-positive bacteria. Other general stress genes have both a sigmaB-dependent induction pathway and a second sigmaB-independent mechanism of stress induction, thereby partially compensating for a sigmaB deficiency in a sigB mutant. In contrast to sigB mutants, null mutations in genes encoding those proteins, such as cIpP or cIpC, cause extreme sensitivity to salt or heat.     

The human homologue of the retroviral oncogene qin maps to chromosome 14q13

Chromosomal mapping of the human QIN gene (renamed FKH2 by the Human Genome Organization Nomenclature Committee) was initially accomplished by correlation of the presence of the QIN locus with specific chromosome regions in a rodent-human hybrid panel. This analysis revealed that the human QIN gene maps to chromosome region 14q11.2-->14q32, between the TCR and IGH loci. Further analysis by fluorescence in situ hybridization techniques with a human QIN genomic clone refined the human QIN gene localization to 14q13.     

A new Graves disease-susceptibility locus maps to chromosome 20q11.2. International Consortium for the Genetics of Autoimmune Thyroid Disease

The autoimmune thyroid diseases (AITDs) include two related disorders, Graves disease (GD) and Hashimoto thyroiditis, in which perturbations of immune regulation result in an immune attack on the thyroid gland. The AITDs are multifactorial and develop in genetically susceptible individuals. However, the genes responsible for this susceptibility remain unknown. Recently, we initiated a whole-genome linkage study of patients with AITD, in order to identify their susceptibility genes. We studied a data set of 53 multiplex, multigenerational AITD families (323 individuals), using highly polymorphic and densely spaced microsatellite markers (intermarker distance <10 cM). Linkage analysis was performed by use of two-point and multipoint parametric methods (classic LOD-score analysis). While studying chromosome 20, we found a locus on chromosome 20q11.2 that was strongly linked to GD. A maximum two-point LOD score of 3.2 was obtained at marker D20S195, assuming a recessive mode of inheritance and a penetrance of.3. The maximum nonparametric LOD score was 2.4 (P=.00043); this score also was obtained at marker D20S195. Multipoint linkage analysis yielded a maximum LOD score of 3.5 for a 6-cM interval between markers D20S195 and D20S107. There was no evidence for heterogeneity in our sample. In our view, these results indicate strong evidence for linkage and suggest the presence of a major GD-susceptibility gene on chromosome 20q11.2.     

Identification of the chromosome 14 origin of a C-negative marker associated with a 14q32 deletion by chromosome painting

A constitutional chromosome 14 rearrangement was observed in a female with a psychodevelopmental disorder. Karyotype analysis using a variety of chromosome techniques, QFQ, GTG, CBG, Ag-NOR and DA-DAPI, showed a deletion of chromosome 14q32.1-qter region in association with a supernumerary marker chromosome. The marker, resembling a submetacentric, approximately half the size of a G group chromosome is C band and Ag-NOR negative. The heteromorphism of the satellites showed that the deleted chromosome 14 is paternal in origin. Chromosome painting using an Alu-PCR probe specific for the human chromosome 14 and fluorescent in situ hybridization (FISH) showed that the marker contains chromosome 14q32 sequences. It is likely that the marker was generated from the deleted chromosome 14 region through a complex rearrangement.     

Posterior column ataxia with retinitis pigmentosa (AXPC1) maps to chromosome 1q31-q32

OBJECTIVE: To establish a genetic linkage between highly polymorphic microsatellite loci and the disease locus responsible for an autosomal recessive neurodegenerative syndrome that causes posterior column ataxia and retinitis pigmentosa. BACKGROUND: The authors reported previously a genetic syndrome that causes visual impairment, proprioceptive loss, sensory ataxia, and areflexia in affected individuals from a large, inbred family belonging to a sectarian population that has been genetically semi-isolated from mainstream society for several centuries. METHODS: To find the disease locus responsible for this condition, the authors performed a genome-wide search using genetic loci spaced at 10 to 20-cM intervals spanning human chromosomes (chr) 1-22. Pairwise linkage analysis, multipoint linkage analysis, and haplotype reconstruction were used to delineate the candidate region containing the disease gene. RESULTS: After testing 226 loci that covered the entire genome, the authors identified a maximum lod score of 8.94 at a recombination fraction of 0.00 for locus D1S2692. Additional analyses placed the disease gene, AXPC1, in an 8.3-cM interval flanked by markers D1S2692 and D1S414 on chr 1q31-q32. CONCLUSIONS: This study suggests that a single genetic mutation can cause selective degeneration of the posterior columns of the spinal cord and retina. Finding the gene responsible for this syndrome may increase our understanding of the molecular basis of diseases that affect sensory neurons.     

The major locus for multifactorial nonsyndromic cleft lip maps to mouse chromosome 11

Cleft lip with or without cleft palate, CL(P), a common human birth defect, has a genetically complex etiology. An animal model with a similarly complex genetic basis is established in the A/WySn mouse strain, in which 20% of newborns have CL(P). Using a newly created congenic strain, AEJ.A, and SSLP markers, we have mapped a major CL(P)-causing gene derived from the A/WySn strain. This locus, here named clf1 (cleft lip) maps to Chromosome (Chr) 11 to a region having linkage homology with human 17q21-24, supporting reports of association of human CL(P) with the retinoic acid receptor alpha (RARA) locus.     

Hereditary isolated renal magnesium loss maps to chromosome 11q23

Dendritic cells (DC) expanded in the presence of GM-CSF from the bone marrow of C57BL/6 mice process Gram-negative bacteria expressing the model antigen Crl-OVA for peptide presentation on MHC class I molecules. Here we show that presentation of OVA(257-264) processed by DC co-incubated with E. coli expressing Crl-OVA, which contains the Kb-binding OVA(257-264) epitope, occurs by a cytosolic MHC-I presentation pathway. First, we demonstrate the requirement for the transporter associated with antigen processing (TAP) by showing that DC from TAP1-/- mice co-incubated with E. coli expressing Crl-OVA did not result in Kb presentation of OVA(257-264). Second, the proteasome inhibitor MG132 abrogated presentation of OVA(257-264) on Kb when C57BL/6 DC phagocytosed and processed E. coli expressing Crl-OVA. Third, inhibiting protein synthesis using cycloheximide or blocking exocytosis of newly synthesized proteins from the endoplasmic reticulum using brefeldin A abrogated presentation of OVA(257-264) processed from bacteria expressing Crl-OVA by C57BL/6 DC. Finally, peptide regurgitation and loading of OVA(257-264) on neighboring bystander Kb-expressing antigen-presenting cells after BALB/c (H-2d) DC phagocytosed E. coli expressing Crl-OVA could not be detected. Together, these data support a cytosolic MHC-I presentation pathway for OVA(257-264) processed from E. coli expressing Crl-OVA by bone marrow-derived DC.