Genetics of multiple sclerosis [published erratum appears in Hum Mol Genet 1997 Nov;6(12):2189]

Multiple Sclerosis (MS) is a common chronic central nervous system disease in young adults. Relative familial risk appears to be determined largely by genes while population risk is strongly influenced by environmental factors. This is supported by genetic epidemiological studies which also suggest an oligogenic inheritance of susceptibility. The HLA DRB1*1501, DQA1*0102, DQB1 0602 haplotype is associated with the disease but HLA contributes only modestly to overall susceptibility. The results of three genomic searches are concordant with the genetic epidemiology and imply a number of genes with interacting effects will be found. Importantly, no single region has been identified with a major influence on familial risk.      

Mutation of the RET ligand, neurturin, supports multigenic inheritance in Hirschsprung disease [published erratum appears in Hum Mol Genet 1998 Oct;7(11):1831]

Hirschsprung disease (HSCR) is a frequent neurocristopathy characterized by the absence of submucosal and myenteric plexuses in a variable length of the gastrointestinal tract. Pedigrees and segregation analyses suggested the involvement of one or several dominant genes with low penetrance in HSCR. Considering that RET and glial cell line-derived neurotrophic factor (GDNF) mutations have been reported in the disease, we regarded the other RET ligand, neurturin (NTN), as an attractive candidate gene, especially as it shares large homologies with GDNF. Here, we report on the finding of a heterozygous missense NTN mutation in a large non-consanguineous family including four children affected with a severe aganglionosis phenotype extending up to the small intestine. Interestingly, it appears that the NTN mutation reported here is not sufficient to cause HSCR, and this multiplex family also segregates a RET mutation. This cascade of independent and additive genetic events fits well with the multigenic pattern of inheritance expected in HSCR, and further support the role of RET ligands in development of the enteric nervous system.      

The gene responsible for autosomal dominant Doyne's honeycomb retinal dystrophy (DHRD) maps to chromosome 2p16 [published erratum appears in Hum Mol Genet 1996 Sep;5(9):1390]

Degeneration in the macula region of the retina is a feature of a heterogeneous group of inherited, progressive disorders, causing blinding visual impairment. Autosomal dominant Doyne's honeycomb retinal dystrophy (DHRD) is characterised by the presence of drusen deposits at the level of Bruch's membrane in the macula and around the edge of the optic nerve head. We have studied 63 members of a large, nine-generation British pedigree by linkage analysis. Two-point analysis showed significant linkage to nine markers on the short arm of chromosome 2, a region overlapping that recently reported to be linked to Malattia leventinese. A maximum lod score (Zmax) of 7.29 (theta = 0.0) was obtained at marker locus D2S2251. Haplotype analysis of recombination events localised the disease to a 5 cM region between marker loci D2S2316 and D2S378. Striking clinical similarities between DHRD and the more common condition age-related macular degeneration (ARMD) suggest that the disease gene at this locus could be considered as the most likely candidate in future studies on ARMD.      

The domain encoded by exon 2 of the survival motor neuron protein mediates nucleic acid binding [published erratum appears in Hum Mol Genet 1998 Oct;7(11):1831]

Spinal muscular atrophy (SMA) is a motor neuron disorder resulting from anterior horn cell death. Survival motor neuron ( SMN ) is the SMA- determining gene and is deleted or gene converted in >95% of SMA patients. The SMN protein has a role in spliceosomal snRNP biogenesis and has therefore been implicated indirectly in general cellular RNA processing due to its unique sub-nuclear localization within structures termed 'gems', which co-localize with spliceosomal factors within coiled bodies. In this report, direct SMN RNA-binding activity, in addition to ssDNA and dsDNA binding is demonstrated. The region of SMN encoded by exon 2 is necessary and sufficient to mediate its nucleic acid-binding activities. This domain is homologous to several nucleic acid-binding factors, including several high mobility group (HMG) proteins. Additionally, previously reported SMN missense mutations isolated from SMA patients demonstrated reduced RNA-binding activity, suggesting that nucleic acid binding is functionally significant.      

Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma [published erratum appears in Hum Mol Genet 1999 May;8(5):943]

Desmosomes are highly organized intercellular adhesive junctions that are particularly prominent in epidermis and other tissues experiencing mechanical stress. Desmoplakin, a constitutive component of the desmosomal plaque, is the most abundant protein present in such junctions and plays a critical role in linking the intermediate filament network to the plasma membrane in these tissues. Here we report the first mutation in the gene encoding desmoplakin. The identified mutation, resulting in a null allele and haploinsufficiency, was observed in genomic DNA from a kindred with the dominantly inherited skin disorder, striate palmoplantar keratoderma. Affected individuals had a linear pattern of skin thickening on the fingers and palms and circumscribed areas of skin thickening on the soles. Affected skin demonstrated loosening of intercellular connections, disruption of desmosome-keratin intermediate filament interactions and a proportion of rudimentary desmosomal structures. The disorder mapped to chromosome 6p21 with a maximum lod score of 10.67. The mutation was a heterozygous C-->T transition in exon 4 of the desmoplakin gene and predicted a premature termination codon in the N-terminal region of the peptide. This is the first reported mutation of desmo-plakin and also the first inherited skin disorder in which haploinsufficiency of a structural component has been implicated. It identifies dosage of desmoplakin as critical in maintaining epidermal integrity.      

Mutations in the palmitoyl-protein thioesterase gene (PPT; CLN1) causing juvenile neuronal ceroid lipofuscinosis with granular osmiophilic deposits [published erratum appears in Hum Mol Genet 1998 Apr;7(4):765]

A subtype of neuronal ceroid lipofuscinosis (NCL) is well recognized which has a clinical course consistent with juvenile NCL (JNCL) but the ultrastructural characteristics of infantile NCL (INCL): granular osmiophilic deposits (GROD). Evidence supporting linkage of this phenotype, designated vJNCL/GROD, to the INCL region of chromosome 1p32 was demonstrated (pairwise lod score with D1S211 , Z max = 2.63, straight theta = 0.00). The INCL gene, palmitoyl-protein thioesterase (PPT ; CLN1), was therefore screened for mutations in 11 vJNCL/GROD families. Five mutations in the PPT gene were identified: three missense mutations, Thr75Pro, Asp79Gly, Leu219Gln, and two nonsense mutations, Leu10STOP and Arg151STOP. The missense mutation Thr75Pro accounted for nine of the 22 disease chromosomes analysed and the nonsense mutation Arg151STOP for seven. Nine out of 11 patients were shown to combine a missense mutation on one disease chromosome with a nonsense mutation on the other. Mutations previously identified in INCL were not observed in vJNCL/GROD families. Thioesterase activity in peripheral blood lymphoblast cells was found to be markedly reduced in vJNCL/GROD patients compared with controls. These results demonstrate that this subtype of JNCL is allelic to INCL and further emphasize the correlation which exists between genetic basis and ultrastructural changes in the NCLs.      

WHSC1, a 90 kb SET domain-containing gene, expressed in early development and homologous to a Drosophila dysmorphy gene maps in the Wolf-Hirschhorn syndrome critical region and is fused to IgH in t(4;14) multiple myeloma [published erratum appears in Hum Mol Genet 1998 Sep;7(9):1527]

Wolf-Hirschhorn syndrome (WHS) is a malformation syndrome associated with a hemizygous deletion of the distal short arm of chromosome 4 (4p16.3). The smallest region of overlap between WHS patients, the WHS critical region, has been confined to 165 kb, of which the complete sequence is known. We have identified and studied a 90 kb gene, designated as WHSC1 , mapping to the 165 kb WHS critical region. This 25 exon gene is expressed ubiquitously in early development and undergoes complex alternative splicing and differential polyadenylation. It encodes a 136 kDa protein containing four domains present in other developmental proteins: a PWWP domain, an HMG box, a SET domain also found in the Drosophila dysmorphy gene ash -encoded protein, and a PHD-type zinc finger. It is expressed preferentially in rapidly growing embryonic tissues, in a pattern corresponding to affected organs in WHS patients. The nature of the protein motifs, the expression pattern and its mapping to the critical region led us to propose WHSC1 as a good candidate gene to be responsible for many of the phenotypic features of WHS. Finally, as a serendipitous finding, of the t(4;14) (p16.3;q32.3) translocations recently described in multiple myelomas, at least three breakpoints merge the IgH and WHSC1 genes, potentially causing fusion proteins replacing WHSC1 exons 1-4 by the IgH 5'-VDJ moiety.      

Analysis of molecular variance (AMOVA) of Y-chromosome-specific microsatellites in two closely related human populations [published erratum appears in Hum Mol Genet 1997 May;6(5):828]

The analysis of seven Y-chromosome-specific microsatellite loci revealed a high level of polymorphism in two closely related human populations (Dutch, n = 89, and German, n = 70). Four of these loci were found to generate at least 77 different haplotypes, only 15 of which were shared by the two populations. These results demonstrate that highly informative PCR-based DNA typing of the Y chromosome is now feasible. Assuming a stepwise mutation model, a network comprising all minimum spanning evolutionary trees connecting the haplotypes was constructed. Analysis of molecular variance based upon this network indicated that the within-population heterogeneity with respect to haplotype descent was significantly smaller than the between-population heterogeneity, suggesting that males were more closely related to males from their own population as opposed to males from the other population. These findings suggest that Y-chromosomal microsatellites might be very useful not only for forensic purposes but also in association studies of multifactorial traits, allowing the characterization of the level of genetic distinctiveness of supposedly inbred or isolated populations and discrimination even between closely related populations.      

Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France. The French Familial Melanoma Study Group [published erratum appears in Hum Mol Genet 1998 May;7(5):941]

Germline mutations in the p16 and CDK4 genes have been reported in a subset of melanoma pedigrees, but their prevalence is not well known. We searched for such germline mutations in 48 French melanoma-prone families selected according to two major criteria: families with at least three affected members (n = 20) or families with two affected members, one of them affected before the age of 50 (n = 28), and one additional minor criterion. Sixteen different p16 germline mutations were found in 21 families, while one germline mutation, Arg24His, was detected in the CDK4 gene. The frequency of p16 gene mutation in our sample (44%) is among the highest rates yet reported and the CDK4 mutation is the second mutation detected in this gene worldwide. In summary, our results show frequent involvement of the p16 gene in familial melanoma and confirm the role of the CDK4 gene as a melanoma- predisposing gene.      

Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin [published erratum appears in Hum Mol Genet 1999 May;8(5):943]

Huntington's disease (HD) is an inherited, neurodegenerative disorder caused by the expansion of a glutamine repeat in the N-terminus of the huntingtin protein. To gain insight into the pathogenesis of HD, we generated transgenic mice that express a cDNA encoding an N-terminal fragment (171 amino acids) of huntingtin with 82, 44 or 18 glutamines. Mice expressing relatively low steady-state levels of N171 huntingtin with 82 glutamine repeats (N171-82Q) develop behavioral abnormalities, including loss of coordination, tremors, hypokinesis and abnormal gait, before dying prematurely. In mice exhibiting these abnormalities, diffuse nuclear labeling, intranuclear inclusions and neuritic aggregates, all immunoreactive with an antibody to the N-terminus (amino acids 1-17) of huntingtin (AP194), were found in multiple populations of neurons. None of these behavioral or pathological phenotypes were seen in mice expressing N171-18Q. These findings are consistent with the idea that N-terminal fragments of huntingtin with a repeat expansion are toxic to neurons, and that N-terminal fragments are prone to form both intranuclear inclusions and neuritic aggregates.      

Analysis of germline mutation spectra at the Huntington's disease locus supports a mitotic [correction of amitotic] mutation mechanism [published erratum appears in Hum Mol Genet 1999 Apr;8(4):717]

Trinucleotide repeat disease alleles can undergo 'dynamic' mutations in which repeat number may change when a gene is transmitted from parent to offspring. By typing >3500 sperm, we determined the size distribution of Huntington's disease (HD) germline mutations produced by 26 individuals from the Venezuelan cohort with CAG/CTG repeat numbers ranging from 37 to 62. Both the mutation frequency and mean change in allele size increased with increasing somatic repeat number. The mutation frequencies averaged 82% and, for individuals with at least 50 repeats, 98%. The extraordinarily high mutation frequency levels are most consistent with a mutation process that occurs throughout germline mitotic divisions, rather than resulting from a single meiotic event. In several cases, the mean change in repeat number differed significantly among individuals with similar somatic allele sizes. This individual variation could not be attributed to age in a simple way or to ' cis ' sequences, suggesting the influence of genetic background or other factors. A familial effect is suggested in one family where both the father and son gave highly unusual spectra compared with other individuals matched for age and repeat number. A statistical model based on incomplete processing of Okazaki fragments during DNA replication was found to provide an excellent fit to the data but variation in parameter values among individuals suggests that the molecular mechanism might be more complex.      

Association between atopic asthma and a coding variant of Fc epsilon RI beta in a Japanese population [published erratum appears in Hum Mol Genet 1996 Dec;5(12):2068]

A genetic association study was performed with coding variants of Fc epsilon RI beta in relation to atopic and non-atopic asthma in a Japanese population (n = 400). A coding variant of Gly237Glu in exon 7 of Fc epsilon RI beta gene showed association with atopic asthma (OR = 3.00, chi 2 = 5.10, p < 0.03), but not with non-atopic asthma; this was seen particularly in childhood asthma (OR = 3.92, chi 2 = 8.66, p < 0.005). This variant is also associated with very high total serum IgE levels (> mean + 3 SD, OR = 8.56, chi 2 = 46.2, p < 0.0001), but not any allergen specific IgE. However, Leu181lle, another variant of Fc epsilon RI beta related to atopy in British and Australian populations, was not found in this Japanese population. These results suggest that variants of Fc epsilon RI beta may be an important genetic cause of the atopic asthma.      

Evolution of the human RH (rhesus) blood group genes: a 50 year old prediction (partially) fulfilled [published erratum appears in Hum Mol Genet 1997 Aug;6(8):1390]

Almost exactly 50 years ago, R. A. Fisher and R. Race proposed a model for the evolution of the RH (rhesus) genes in which the less common haplotypes were derived from the commoner ones by recombination, and in which the gene order was D-C-E. No direct-evidence bearing on this model was available then, and has not been until now. Here we present evidence for non-reciprocal intergenic exchange (gene conversion) occurring once in human history to generate the common RHCE allele, Ce. We have also used new polymorphisms to construct haplotypes which suggest that intragenic recombination played a major role in the generation of the less common haplotypes, but only if RHD lies 3' of RHCE, i.e. the order is C-E-D. We provide both genetic and physical evidence supporting this arrangement.      

Molecular and biochemical analysis of protective protein/cathepsin A mutations: correlation with clinical severity in galactosialidosis [published erratum appears in Hum Mol Genet 1997 Jan;6(1):146]

Mutations in the gene encoding lysosomal protective protein/cathepsin A (PPCA) are the cause of the lysosomal disorder galactosialidosis (GS). Depending on age of onset and severity of the symptoms, patients present with either an early infantile (EI), a late infantile (LI), or a juvenile/adult (J/A) form of the disease. To study genotype-phenotype correlation in this disorder, we have analyzed the mutations in the PPCA gene of eight clinically different patients. In two EI and one J/A patient, we have identified four novel point mutations (Val104Met, Leu208Pro, Gly411Ser and Ser23Tyr), that prevent phosphorylation and, hence, lysosomal localization and maturation of the mutant precursors. Two amino acid substitutions (Phe412Val and Tyr221Asn) are shared by five LI patients. These mutations appear to be pathognomonic for this phenotype, and determine the clinical outcome depending on whether they are present together or in combination with other mutations. The latter include a single base deletion and a novel amino acid change (Met378Thr), which generates an additional glycosylation site. Within the LI group, patients carrying the Phe412Val mutation are clinically more severe than those with the Tyr221Asn substitution. This is in agreement with the biochemical behavior of the Asn221-mutant protein, that is, like the Phe412Val protein, phosphorylated, routed to lysosomes and proteolytically processed, but its intralysosomal stability is intermediate between that of wild-type PPCA and Val412- PPCA. Overall, these results may explain the clinical heterogeneity observed in GS patients and may help to correlate mutant allelic combinations with specific clinical phenotypes.      

Mapping of a second locus for lamellar ichthyosis to chromosome 2q33-35 [published erratum appears in Hum Mol Genet 1996 Jun;5(6):862-3]

Lamellar ichthyosis (LI) is an inherited autosomal recessive disorder of cornification. It was recently demonstrated to result from deleterious mutations in the transglutaminase 1 (TGM1) gene. However, the disease was shown to be genetically heterogeneous, since some families were found to be unlinked to TGM1. Homozygosity mapping on three consanguinous families originating from Morocco shows (i) absence of linkage with TGM1 and other regions of the genome containing genes involved in cornification, and (ii) location of a second disease- causing gene on chromosome 2q33-35. A maximum two-point lodscore of 7.60 was obtained with D2S157 for theta = 0. The analysis of recombination events places the gene within a 7-8 cM interval. Additional consanguinous pedigrees were also demonstrated to be unlinked both to TGM1 and to 2q33-35, suggesting the existence of at least a third disease-causing gene.