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1.
Wei-Ling Lee A. Tay Hian-Tat Ong Li-Meng Goh Anthony P. Monaco Pierre Szepetowski 《Human genetics》1998,103(5):608-612
We have studied one family of Chinese origin, in which benign infantile convulsions and paroxysmal choreoathetosis (of the
dystonic form) were co-inherited as a single autosomal dominant trait. This association is specific to ICCA syndrome, which
we have recently described in four French families. Some patients in the new family also exhibit recurrence of epileptic seizures
at a much later age, making the ICCA syndrome in this family atypical. DNA samples isolated from this family of 22 members
(9 affected) have been tested with genetic markers at chromosome 16p12-q12, in which region the ICCA syndrome has previously
been linked. Confirmation of linkage to this pericentromeric region of human chromosome 16 has been obtained and no critical
meiotic recombination event has been detected in the ICCA region. This result suggests that, in contrast to marked clinical
heterogeneity, the association of infantile convulsions with paroxysmal dyskinetic movements could be genetically homogeneous.
Received: 21 July 1998 / Accepted: 12 September 1998 相似文献
2.
Benign familial infantile convulsions: mapping of a novel locus on chromosome 2q24 and evidence for genetic heterogeneity 总被引:18,自引:0,他引:18
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Malacarne M Gennaro E Madia F Pozzi S Vacca D Barone B dalla Bernardina B Bianchi A Bonanni P De Marco P Gambardella A Giordano L Lispi ML Romeo A Santorum E Vanadia F Vecchi M Veggiotti P Vigevano F Viri F Bricarelli FD Zara F 《American journal of human genetics》2001,68(6):1521-1526
In 1997, a locus for benign familial infantile convulsions (BFIC) was mapped to chromosome 19q. Further data suggested that this locus is not involved in all families with BFIC. In the present report, we studied eight Italian families and mapped a novel BFIC locus within a 0.7-cM interval of chromosome 2q24, between markers D2S399 and D2S2330. A maximum multipoint HLOD score of 6.29 was obtained under the hypothesis of genetic heterogeneity. Furthermore, the clustering of chromosome 2q24-linked families in southern Italy may indicate a recent founder effect. In our series, 40% of the families are linked to neither chromosome 19q or 2q loci, suggesting that at least three loci are involved in BFIC. This finding is consistent with other autosomal dominant idiopathic epilepsies in which different genes were found to be implicated. 相似文献
3.
4.
Tomita Ha Nagamitsu S Wakui K Fukushima Y Yamada K Sadamatsu M Masui A Konishi T Matsuishi T Aihara M Shimizu K Hashimoto K Mineta M Matsushima M Tsujita T Saito M Tanaka H Tsuji S Takagi T Nakamura Y Nanko S Kato N Nakane Y Niikawa N 《American journal of human genetics》1999,65(6):1688-1697
Paroxysmal kinesigenic choreoathetosis (PKC), the most frequently described type of paroxysmal dyskinesia, is characterized by recurrent, brief attacks of involuntary movements induced by sudden voluntary movements. Some patients with PKC have a history of infantile afebrile convulsions with a favorable outcome. To localize the PKC locus, we performed genomewide linkage analysis on eight Japanese families with autosomal dominant PKC. Two-point linkage analysis provided a maximum LOD score of 10.27 (recombination fraction [theta] =.00; penetrance [p] =.7) at marker D16S3081, and a maximum multipoint LOD score for a subset of markers was calculated to be 11.51 (p = 0.8) at D16S3080. Haplotype analysis defined the disease locus within a region of approximately 12.4 cM between D16S3093 and D16S416. P1-derived artificial chromosome clones containing loci D16S3093 and D16S416 were mapped, by use of FISH, to 16p11.2 and 16q12.1, respectively. Thus, in the eight families studied, the chromosomal localization of the PKC critical region (PKCR) is 16p11.2-q12.1. The PKCR overlaps with a region responsible for "infantile convulsions and paroxysmal choreoathetosis" (MIM 602066), a recently recognized clinical entity with benign infantile convulsions and nonkinesigenic paroxysmal dyskinesias. 相似文献
5.
Roll P Sanlaville D Cillario J Labalme A Bruneau N Massacrier A Délepine M Dessen P Lazar V Robaglia-Schlupp A Lesca G Jouve E Rudolf G Rochette J Lathrop GM Szepetowski P 《PloS one》2010,5(10):e13750
Background
Benign infantile convulsions and paroxysmal dyskinesia are episodic cerebral disorders that can share common genetic bases. They can be co-inherited as one single autosomal dominant trait (ICCA syndrome); the disease ICCA gene maps at chromosome 16p12-q12. Despite intensive and conventional mutation screening, the ICCA gene remains unknown to date. The critical area displays highly complicated genomic architecture and is the site of deletions and duplications associated with various diseases. The possibility that the ICCA syndrome is related to the existence of large-scale genomic alterations was addressed in the present study.Methodology/Principal Findings
A combination of whole genome and dedicated oligonucleotide array comparative genomic hybridization coupled with quantitative polymerase chain reaction was used. Low copy number of a region corresponding to a genomic variant (Variation_7105) located at 16p11 nearby the centromere was detected with statistical significance at much higher frequency in patients from ICCA families than in ethnically matched controls. The genomic variant showed no apparent difference in size and copy number between patients and controls, making it very unlikely that the genomic alteration detected here is ICCA-specific. Furthermore, no other genomic alteration that would directly cause the ICCA syndrome in those nine families was detected in the ICCA critical area.Conclusions/Significance
Our data excluded that inherited genomic deletion or duplication events directly cause the ICCA syndrome; rather, they help narrowing down the critical ICCA region dramatically and indicate that the disease ICCA genetic defect lies very close to or within Variation_7105 and hence should now be searched in the corresponding genomic area and its surrounding regions. 相似文献6.
P Szepetowski J Rochette P Berquin C Piussan G M Lathrop A P Monaco 《American journal of human genetics》1997,61(4):889-898
Benign infantile familial convulsions is an autosomal dominant disorder characterized by nonfebrile seizures, with the first attack occurring at age 3-12 mo. It is one of the rare forms of epilepsy that are inherited as monogenic Mendelian traits, thus providing a powerful tool for mapping genes involved in epileptic syndromes. Paroxysmal choreoathetosis is an involuntary-movement disorder characterized by attacks that occur spontaneously or are induced by a variety of stimuli. Classification is still elusive, and the epileptic nature of this movement disorder has long been discussed and remains controversial. We have studied four families from northwestern France in which benign infantile convulsions was inherited as an autosomal dominant trait together with variably expressed paroxysmal choreoathetosis. The human genome was screened with microsatellite markers regularly spaced, and strong evidence of linkage for the disease gene was obtained in the pericentromeric region of chromosome 16, with a maximum two-point LOD score, for D16S3133, of 6.76 at a recombination fraction of 0. Critical recombinants narrowed the region of interest to a 10-cM interval around the centromere. Our study provides the first genetic evidence for a common basis of convulsive and choreoathetotic disorders and will help in the understanding and classification of paroxysmal neurological syndromes. 相似文献
7.
Search for alpha4 and alpha7 nicotinic acetylcholine receptor markers in a pedigree of benign familial infantile convulsions (BFIC) 总被引:4,自引:0,他引:4
In this study we investigate the possible involvement of the recently reported locus for benign familial infantile convulsions (BFIC) in human chromosome 19 and that of the neuronal acetylcholine receptor 4 (CHRNA4) and 7 (CHRNA7) subunits in a family with at least twelve clinically diagnosed cases of BFIC. Six polymorphic microsatellite markers covering the BFIC locus on chromosomal region 19q, one marker for CHRNA4 (chromosome 20) and two for CHRNA7 (chromosome 15) were used for the screening. The two-point lod score analysis showed no evidence of BFIC phenotype on chromosome 19. Similarly, when markers for chromosome 20 (CHRNA4 intron1, Amplimer: CHRNA4. PCR.1) and chromosome 15 (D15S165 and D15S1010) were used, score analysis showed no indication of linkage. The most likely interpretation of these results is that BFIC is a genetically heterogeneous form of epilepsy. 相似文献
8.
Heron SE Grinton BE Kivity S Afawi Z Zuberi SM Hughes JN Pridmore C Hodgson BL Iona X Sadleir LG Pelekanos J Herlenius E Goldberg-Stern H Bassan H Haan E Korczyn AD Gardner AE Corbett MA Gécz J Thomas PQ Mulley JC Berkovic SF Scheffer IE Dibbens LM 《American journal of human genetics》2012,90(1):152-160
Benign familial infantile epilepsy (BFIE) is a self-limited seizure disorder that occurs in infancy and has autosomal-dominant inheritance. We have identified heterozygous mutations in PRRT2, which encodes proline-rich transmembrane protein 2, in 14 of 17 families (82%) affected by BFIE, indicating that PRRT2 mutations are the most frequent cause of this disorder. We also report PRRT2 mutations in five of six (83%) families affected by infantile convulsions and choreoathetosis (ICCA) syndrome, a familial syndrome in which infantile seizures and an adolescent-onset movement disorder, paroxysmal kinesigenic choreoathetosis (PKC), co-occur. These findings show that mutations in PRRT2 cause both epilepsy and a movement disorder. Furthermore, PRRT2 mutations elicit pleiotropy in terms of both age of expression (infancy versus later childhood) and anatomical substrate (cortex versus basal ganglia). 相似文献
9.
Background
Mutations in the PRRT2 gene have been identified as the major cause of benign familial infantile epilepsy (BFIE), paroxysmal kinesigenic dyskinesia (PKD) and infantile convulsions with paroxysmal choreoathetosis/dyskinesias (ICCA). Here, we analyzed the phenotypes and PRRT2 mutations in Chinese families with BFIE and ICCA.Methods
Clinical data were collected from 22 families with BFIE and eight families with ICCA. PRRT2 mutations were screened using PCR and direct sequencing.Results
Ninety-five family members were clinically affected in the 22 BFIE families. During follow-up, two probands had one seizure induced by diarrhea at the age of two years. Thirty-one family members were affected in the eight ICCA families, including 11 individuals with benign infantile epilepsy, nine with PKD, and 11 with benign infantile epilepsy followed by PKD. Two individuals in one ICCA family had PKD or ICCA co-existing with migraine. One affected member in another ICCA family had experienced a fever-induced seizure at 7 years old. PRRT2 mutations were detected in 13 of the 22 BFIE families. The mutation c.649_650insC (p.R217PfsX8) was found in nine families. The mutations c.649delC (p.R217EfsX12) and c.904_905insG (p.D302GfsX39) were identified in three families and one family, respectively. PRRT2 mutations were identified in all eight ICCA families, including c.649_650insC (p.R217PfsX8), c.649delC (p.R217EfsX12), c.514_517delTCTG (p.S172RfsX3) and c.1023A?>?T (X341C). c.1023A?>?T is a novel mutation predicted to elongate the C-terminus of the protein by 28 residues.Conclusions
Our data demonstrated that PRRT2 is the major causative gene of BFIE and ICCA in Chinese families. Site c.649 is a mutation hotspot: c.649_650insC is the most common mutation, and c.649delC is the second most common mutation in Chinese families with BFIE and ICCA. As far as we know, c.1023A?>?T is the first reported mutation in exon 4 of PRRT2. c.649delC was previously reported in PKD, ICCA and hemiplegic migraine families, but we further detected it in BFIE-only families. c.904_905insG was reported in an ICCA family, but we identified it in a BFIE family. c.514_517delTCTG was previously reported in a PKD family, but we identified it in an ICCA family. Migraine and febrile seizures plus could co-exist in ICCA families.10.
Ortrud Steinlein Volker Schuster Christine Fischer Martin Häussier 《Human genetics》1995,95(4):411-415
The syndrome of benign familial neonatal convulsions (BFNC) is a rare, autosomal dominant form of epilepsy. It is characterized by spontanous seizures beginning within the first 6 months of life. In the majority of families linkage is to chromosome 20q markers. Based on the linkage results in one large BFNC kindred, genetic heterogeneity and existence of a second locus on chromosome 8 have been suggested. Here we report on a second BFNC family in which linkage to the EBN1 locus on chromosome 20q was excluded, confirming the genetic heterogeneity of this disorder. All affected family members experienced onset of seizures before the age of 2 months. Three BFNC subjects showed subsequent epileptic seizures after 12 months of age, showing that the risk of subsequent epilepsy is not restricted to the chromosome 20q linked BFNC families. A lod score of 0.99 was obtained with the marker D8S274, suggesting linkage to chromosome 8. 相似文献
11.
R C Levitt A Olckers S Meyers J E Fletcher H Rosenberg H Isaacs D A Meyers 《Genomics》1992,14(3):562-566
Malignant hyperthermia susceptibility is a lethal autosomal dominant disorder of skeletal muscle metabolism that is triggered by all potent inhalation anesthetic gases. Recent linkage studies suggest a genetic locus for this disorder on 19q13.1. We have previously reported three unrelated families diagnosed with MHS that are unlinked to markers surrounding this locus on 19q13.1. In this report we extend these observations and present linkage studies on 16 MHS families. Four families (25%) were found linked to the region 19q12-q13.2 (Zmax = 2.96 with the ryanodine receptor at theta = 0.0). Five families (31%) were found closely linked to the anonymous marker NME1 (previously designated NM23) on chromosome 17q11.2-q24 (Zmax = 3.26 at theta = 0.0). Two families (13%) were clearly unlinked to either of these chromosomal regions. In five additional families, data were insufficient to determine their linkage status (they were potentially linked to two or more sites). The results of our heterogeneity analyses are consistent with the hypothesis that MHS can be caused in humans by any one of at least three distinct genetic loci. Furthermore, we provide preliminary linkage data suggesting the localization of a gene in human MHS to 17q11.2-q24 (MHS2), with a gene frequency of this putative locus approximately equal to that of the MHS1 locus on 19q. 相似文献
12.
13.
T L Young S M Ronan A B Alvear S C Wildenberg W S Oetting L D Atwood D J Wilkin R A King 《American journal of human genetics》1998,63(5):1419-1424
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. 相似文献
14.
Evidence that a locus for familial high myopia maps to chromosome 18p. 总被引:38,自引:0,他引:38
T L Young S M Ronan L A Drahozal S C Wildenberg A B Alvear W S Oetting L D Atwood D J Wilkin R A King 《American journal of human genetics》1998,63(1):109-119
Myopia, or nearsightedness, is the most common human eye disorder. A genomewide screen was conducted to map the gene(s) associated with high, early-onset, autosomal dominant myopia. Eight families that each included two or more individuals with >=-6.00 diopters (D) myopia, in two or more successive generations, were identified. Myopic individuals had no clinical evidence of connective-tissue abnormalities, and the average age at diagnosis of myopia was 6.8 years. The average spherical component refractive error for the affected individuals was -9.48 D. The families contained 82 individuals; of these, DNA was available for 71 (37 affected). Markers flanking or intragenic to the genes for Stickler syndrome types 1 and 2 (chromosomes 12q13.1-q13.3 and 6p21.3, respectively), Marfan syndrome (chromosome 15q21.1), and juvenile glaucoma (chromosome 1q21-q31) were also analyzed. No evidence of linkage was found for markers for the Stickler syndrome types 1 and 2, the Marfan syndrome, or the juvenile glaucoma loci. After a genomewide search, evidence of significant linkage was found on chromosome 18p. The maximum LOD score was 9.59, with marker D18S481, at a recombination fraction of .0010. Haplotype analysis further refined this myopia locus to a 7.6-cM interval between markers D18S59 and D18S1138 on 18p11.31. 相似文献
15.
Mapping of a gene determining familial partial epilepsy with variable foci to chromosome 22q11-q12 总被引:10,自引:0,他引:10
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Xiong L Labuda M Li DS Hudson TJ Desbiens R Patry G Verret S Langevin P Mercho S Seni MH Scheffer I Dubeau F Berkovic SF Andermann F Andermann E Pandolfo M 《American journal of human genetics》1999,65(6):1698-1710
We identified two large French-Canadian families segregating a familial partial epilepsy syndrome with variable foci (FPEVF) characterized by mostly nocturnal seizures arising from frontal, temporal, and occasionally occipital epileptic foci. There is no evidence for structural brain damage or permanent neurological dysfunction. The syndrome is inherited as an autosomal dominant trait with incomplete penetrance. We mapped the disease locus to a 3. 8-cM interval on chromosome 22q11-q12, between markers D22S1144 and D22S685. Using the most conservative diagnostic scheme, the maximum cumulative LOD score was 6.53 at recombination fraction (straight theta) 0 with D22S689. The LOD score in the larger family was 5.34 at straight theta=0 with the same marker. The two families share an identical linked haplotype for >/=10 cM, including the candidate interval, indicating a recent founder effect. A severe phenotype in one of the probands may be caused by homozygosity for the causative mutation, as suggested by extensive homozygosity for the linked haplotype and a bilineal family history of epilepsy. An Australian family with a similar phenotype was not found to link to chromosome 22, indicating genetic heterogeneity of FPEVF. 相似文献
16.
A Bedouin kindred with infantile nephronophthisis demonstrates linkage to chromosome 9 by homozygosity mapping. 总被引:3,自引:2,他引:1
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N B Haider R Carmi H Shalev V C Sheffield D Landau 《American journal of human genetics》1998,63(5):1404-1410
A novel type of infantile nephronophthisis was identified in an extended Bedouin family from Israel. This disease has an autosomal recessive mode of inheritance, with the phenotypic presentation ranging from a Potter-like syndrome to hyperechogenic kidneys, renal insufficiency, hypertension, and hyperkalemia. Affected individuals show rapid deterioration of kidney function, leading to end-stage renal failure within 3 years. Histopathologic examination of renal tissue revealed variable findings, ranging from infantile polycystic kidneys to chronic tubulointerstitial nephritis, fibrosis, and cortical microcysts. A known familial juvenile nephronophthisis locus on chromosome 2q13 and autosomal recessive polycystic kidney disease on chromosome 6p21.1-p12 were excluded by genetic linkage analysis. A genomewide screen for linkage was conducted by searching for a locus inherited by descent in all affected individuals. Pooled DNA samples from parents and unaffected siblings and individual DNA samples from four affected individuals were used as PCR templates with trinucleotide- and tetranucleotide-repeat polymorphic markers. Using this approach, we identified linkage to infantile nephronophthisis for markers on chromosome 9q22-31. The disorder maps to a 12.9-cM region flanked by markers D9S280 and GGAT3G09. 相似文献
17.
Genetic localization of a newly recognized autosomal dominant limb-girdle muscular dystrophy with cardiac involvement (LGMD1B) to chromosome 1q11-21. 总被引:6,自引:1,他引:5
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A J van der Kooi M van Meegen T M Ledderhof E M McNally M de Visser P A Bolhuis 《American journal of human genetics》1997,60(4):891-895
Limb-girdle muscular dystrophy (LGMD) constitutes a clinically and genetically heterogeneous group of myogenic disorders with a limb-girdle distribution of weakness. One autosomal dominant family, LGMD1A, has been linked to chromosome 5q, whereas in other autosomal dominant families linkage to this chromosome has been excluded. We studied 58 members of three families with a newly recognized autosomal dominantly inherited LGMD with cardiac involvement. A search with highly polymorphic microsatellite markers was carried out. The gene for this newly recognized dominant form of LGMD was located on chromosome 1q11-21, with a combined maximum two-point LOD score >12 at theta = 0. 相似文献
18.
Silver syndrome is a rare variant of autosomal dominant complicated hereditary spastic paraparesis (HSP), in which spasticity of the lower limbs is accompanied by amyotrophy of the hands and occasionally also the lower limbs. The disease locus has been mapped to chromosome 11q12-q14. We report four Austrian families presenting with the typical clinical features of Silver syndrome. Sixteen individuals were affected upon clinical and/or electrophysiological examination. Ten persons showed mild to severe spasticity of the lower limbs. Wasting of the small hand muscles was present in nine affected family members of whom three had also gait disturbance. Three further individuals were asymptomatic. Electrophysiological studies showed normal or slightly to moderately slowed motor nerve conduction velocities, reduced amplitudes and occasionally chronodispersion of compound motor action potentials. In one patient, conduction block was observed. Sensory nerve action potentials were usually normal. Molecular genetic studies demonstrate linkage to chromosome 11q12-q14. Haplotype analysis in affected individuals indicates a common ancestor in the four families. By recombination analysis in affected individuals the Silver syndrome candidate gene interval can be reduced from 13 to 5.9 cM and can now be placed between the markers D11S1765 and D11S987. By sequence analysis of affected individuals eight functional and positional candidate genes could be excluded. Our study confirms the existence of the Silver syndrome locus on chromosome 11q12-q14 and provides the first report of nerve conduction velocity studies in Silver syndrome, which demonstrate the presence of a peripheral predominantly motor neuropathy. 相似文献
19.
Linkage of a gene causing familial focal segmental glomerulosclerosis to chromosome 11 and further evidence of genetic heterogeneity. 总被引:18,自引:0,他引:18
M P Winn P J Conlon K L Lynn D N Howell B D Slotterbeck A H Smith F L Graham M Bembe L D Quarles M A Pericak-Vance J M Vance 《Genomics》1999,58(2):113-120
Focal segmental glomerulosclerosis (FSGS) is a pathological entity characterized by proteinuria, nephrotic syndrome, and the progressive loss of renal function. It is a common cause of end-stage renal disease (ESRD). Recently, familial forms of FSGS have been identified. Two families with autosomal dominant FSGS were evaluated for linkage using 351 genomic microsatellite markers. Linkage, multipoint analysis, and tests for heterogeneity were performed on the subsequent results. In addition, three small families were used for haplotype analysis. Evidence for linkage was found on chromosome 11q21-q22 for the largest family, with a maximum lod score of 9.89. The gene is currently localized to an 18-cM area between flanking markers D11S2002 and D11S1986. The disease in a second family was not linked to this locus or to a previously described locus on chromosome 19q13. There were no shared haplotypes among affected individuals in the three smaller families. Our findings demonstrate that genetic heterogeneity is prevalent in FSGS in that at least three genes cause the FSGS phenotype. Identification of the genes that cause familial FSGS will provide valuable insights into the molecular basis and pathophysiology of FSGS. 相似文献
20.
N. G. Laing B. T. Majda P. A. Akkari M. G. Layton J. C. Mulley H. Phillips E. A. Haan S. J. White A. H. Beggs L. M. Kunkel D. M. Groth K. L. Boundy C. S. Kneebone P. C. Blumberg S. D. Wilton M. C. Speer B. A. Kakulas 《American journal of human genetics》1992,50(3):576-583
Nemaline myopathy (NEM) is a neuromuscular disorder characterized by the presence, in skeletal muscle, of nemaline rods composed at least in part of alpha-actinin. A candidate gene and linkage approach was used to localize the gene (NEM1) for an autosomal dominant form (MIM 161800) in one large kindred with 10 living affected family members. Markers on chromosome 19 that were linked to the central core disease gene, a marker at the complement 3 locus, and a marker on chromosome 1 at the alpha-actinin locus exclude these three candidate genes. The family was fully informative for APOA2, which is localized to 1q21-q23. NEM1 was assigned to chromosome 1 by close linkage for APOA2, which is localized to 1q21-q23. NEM1 was assigned to chromosome 1 by close linkage to APOA2, with a lod score of 3.8 at a recombination fraction of 0. Recombinants with NGFB (1p13) and AT3 (1q23-25.1) indicate that NEM1 lies between 1p13 and 1q25.1. In total, 47 loci were investigated on chromosomes 1, 2, 4, 5, 7-11, 14, 16, 17, and 19, with no indications of significant linkage other than to markers on chromosome 1. 相似文献