Autoimmunity in juvenile diabetics and their families.

Pancreatic islet cell, thyroid, and gastric antibodies were studied in 116 young insulin-dependent diabetics and 257 relatives. Seventy-four per cent of the diabetics studied within three months of diagnosis had islet-cell antibodies but only 20% of those studied three years or more after diagnosis. Persistence of these antibodies was associated with a high prevalence of thyrogastric autoimmunity, which suggests that some cases have an aetiology similar to that of "polyendocrine" autoimmune disease. Retinopathy or nephropathy, or both, was present in 10 diabetics, who were all members of "autoimmune" families, in which one or more members had organ-specific antibodies. Nine of the 10 healthy relatives with islet-cell antibodies and all families with more than one diabetic were also in this autoimmune group. These data suggest that an autoimmune factor may contribute to juvenile diabetes and that such autoimmune diabetes has a tendency to run in families and may be more likely to cause complications.     

Unusual clustering of diseases in a Canadian Old Colony (Chortitza) Mennonite kindred and community.

We investigated a large Old Colony (Chortitza) Mennonite kindred with branches across Canada. Six generations of the kindred were traced. There was intermarriage among numerous family members. Insulin-dependent diabetes mellitus (IDDM) was identified in 10 members; all 7 living patients were found to carry the immunogenetic marker HLA-DR4. Nine other close relatives had disorders of carbohydrate metabolism, including gestational diabetes mellitus and non-insulin-dependent diabetes mellitus progressing to insulin use. Ten other relatives had autoimmune diseases, including rheumatoid arthritis, hyperthyroidism, hypothyroidism and multiple sclerosis. Cases of Alport''s syndrome, congenital malformations, inborn errors of metabolism and unusual malignant diseases were also found in the kindred. In the small Alberta community in which the kindred was ascertained there were people of Old Colony Mennonite descent with genetic conditions such as Gilles de la Tourette''s syndrome and congenital malformations, including congenital heart disease. This kindred represents the largest reported familial aggregation of IDDM. This disease and other disorders of carbohydrate metabolism occur in the context of a strong familial predisposition to autoimmune disease. Study of this family may permit empiric testing of proposed models of inheritance of diseases of complex origin such as IDDM. We report this Old Colony (Chortitza) Mennonite community because it is one of the settlements populated by this religious and genetic isolate, which extends across Canada and Central and South America and affords opportunities for the study of both common and rare inherited diseases.     

Family studies in common variable immunodeficiency

The occurrence of cancer, immunodeficiency, and diseases with possible autoimmune aetiology were studied in 355 blood relatives of 12 patients with common variable immunodeficiency (CVID). The family members were identified through the patients and interviewed after completing a questionnaire, their diseases were medically confirmed by local general practitioners. In two families consanguineous marriages were identified with the coefficients of inbreeding of 0.03125 and 0.01563, respectively: one patient, a dizygotic twin of an unaffected sister, was a granddaughter of first cousins, the second patient was the third daughter of second cousins. These cases of CVID strongly support the autosomal recessivity of the underlying genes. One male patient with CVID was shown to be related to a patient with X-linked hypogammaglobulinaemia, both sharing a common carrier. The different clinical courses of their diseases suggest two genetically determined immunodeficiencies and genetic heterogeneity. No family had an unusual clustering of cancer. The occurrence of tumours in the blood relatives of CVID patients was not significantly higher than in the relatives of spouse controls. Immunological examination of 30 first degree relatives of the CVID patients revealed three children (2 males and 1 female) with selective IgA deficiency, in one boy combined with elevated serum IgE level. Four relatives with rheumatoid heart disease, 12 cases of gastric or duodenal ulcer, and 14 relatives with thyroid disease represented the most often encountered diagnoses with a possible autoimmune component in their aetiology.     

Myelocystocele-cloacal exstrophy in a pedigree with a mitochondrial 12S rRNA mutation, aminoglycoside-induced deafness, pigmentary disturbances, and spinal anomalies

A large Filipino-American family with progressive matrilineal hearing loss, premature graying, depigmented patches, and digital anomalies was ascertained through a survey of a spina bifida clinic for neural crest disorders. Deafness followed a matrilineal pattern of inheritance and was associated with the A1555G mutation in the 12S rRNA gene (MTRNR1) in affected individuals as well as unaffected maternal relatives. Several other malformations were found in carriers of the mutation. The proband had a myelocystocele, Arnold-Chiari type I malformation, cloacal exstrophy, and severe early-onset hearing loss. Several family members had premature graying, white forelock, congenital leukoderma with or without telecanthus, somewhat suggestive of a Waardenburg syndrome variant. In addition to the patient with myelocystocele, two individuals had scoliosis and one had segmentation defects of spinal vertebrae. The syndromic characteristics reported here are novel for the mitochondrial A1555G substitution, and may result from dysfunction of mitochondrial genes during early development. However, the mitochondrial A1555G mutation is only rarely associated with neural tube defects as it was not found in a screen of 218 additional individuals with spina bifida, four of whom had congenital hearing loss.     

Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families

Generalized vitiligo is an autoimmune disorder characterized by acquired white patches of skin and overlying hair, the result of loss of melanocytes from involved areas. The most common disorder of pigmentation, vitiligo occurs with a frequency of 0.1-2.0% in various populations. Family clustering of cases is not uncommon, in a non-Mendelian pattern suggestive of multifactorial, polygenic inheritance. We surveyed 2624 vitiligo probands from North America and the UK regarding clinical characteristics, familial involvement, and association with other autoimmune disorders, the largest such survey ever performed. More than 83% of probands were Caucasians, and the frequency of vitiligo appeared approximately equal in males and females. The frequency of vitiligo in probands' siblings was 6.1%, about 18 times the population frequency, suggesting a major genetic component in disease pathogenesis. Nevertheless, the concordance of vitiligo in monozygotic twins was only 23%, indicating that a non-genetic component also plays an important role. Probands with earlier disease onset tended to have more relatives affected with vitiligo, suggesting a greater genetic component in early onset families. The frequencies of six autoimmune disorders were significantly elevated in vitiligo probands and their first-degree relatives: vitiligo itself, autoimmune thyroid disease (particularly hypothyroidism), pernicious anaemia, Addison's disease, systemic lupus erythematosus, and probably inflammatory bowel disease. These associations indicate that vitiligo shares common genetic aetiologic links with these other autoimmune disorders. These results suggest that genomic analysis of families with generalized vitiligo and this specific constellation of associated autoimmune disorders will be important to identify the mechanisms of genetic susceptibility to autoimmunity.     

De novo mutation in the mitochondrial ATP synthase subunit 6 gene (T8993G) with rapid segregation resulting in Leigh syndrome in the offspring

The mutation in the mitochondrial ATP synthase subunit 6 gene (ATP6 T8993G) was identified in a male infant who died at age 15 months of Leigh syndrome. He had 94% mutated mitochondrial DNA (mtDNA) in muscle and 92% in lymphocytes. His mother was healthy but had 37% mutated mtDNA in muscle and 38% in lymphocytes. The proband's brother, who was also healthy, had 44% mutated mtDNA in lymphocytes. No mutated mtDNA was detected in muscle and lymphocytes from the maternal grandmother of the proband or in lymphocytes from 15 other maternal relatives, showing that the first carrier of the ATP6 T8993G mutation in this family was the mother of the proband. This study shows that this point mutation may occur at substantial levels in a carrier of a de novo mutation and rapid segregation with high levels of mutated mtDNA causing neurodegenerative disease may occur in the second generation.     

The mitochondrial tRNA(Ala) T5628C variant may have a modifying role in the phenotypic manifestation of the 12S rRNA C1494T mutation in a large Chinese family with hearing loss

We report here the clinical, genetic, and molecular characterization of a large Han Chinese family with aminoglycoside-induced and nonsyndromic hearing loss. Two and 13 of 66 matrilineal relatives suffered from aminoglycoside-induced and nonsyndromic hearing loss, respectively. These matrilineal relatives exhibited a wide range of severity of hearing loss, varying from profound to normal hearing. In the absence of aminoglycosides, the age-at-onset of hearing impairment in these matrilineal relatives ranged from 13 to 50years. Furthermore, these affected matrilineal relatives shared some common features: bilateral hearing loss of high frequencies and symmetries. Sequence analysis of mitochondrial DNA (mtDNA) in the pedigree identified the homoplasmic 12S rRNA C1494T mutation and other 34 variants belonging to Eastern Asian haplogroup F1. Of these, the variant T5628C occurs at an extremely conserved nucleotide (A31) of tRNA(Ala). This variant converted a very conservative A-U to a G-U base-pairing at AC-stem of this tRNA. The disruption of this base-pairing in tRNAs by mtDNA mutations has been associated with several clinical abnormalities. The alteration of structure of the tRNA(Ala) by the T5628C mutation may lead to a failure in tRNA metabolism and lead to impairment of mitochondrial translation, thereby worsening mitochondrial dysfunctions, caused by the C1494T mutation. Therefore, this mtDNA mutation may influence the phenotypic manifestation of the 12S rRNA C1494T mutation in this Chinese pedigree.     

Maternally transmitted diabetes mellitus associated with the mitochondrial tRNA(Leu(UUR)) A3243G mutation in a four-generation Han Chinese family

We report here the characterization of a four-generation Han Chinese family with maternally transmitted diabetes mellitus. Six (two males/four females) of eight matrilineal relatives in this family exhibited diabetes. The age of onset in diabetes varies from 15 years to 33 years, with an average of 26 years. Two of affected matrilineal relatives also exhibited hearing impairment. Molecular analysis of mitochondrial DNA (mtDNA) showed the presence of heteroplasmic tRNA(Lue(UUR)) A3243G mutation, ranging from 35% to 58% of mutations in blood cells of matrilineal relatives. The levels of heteroplasmic A3243G mutation seem to be correlated with the severity and age-at-onset of diabetes in this family. Sequence analysis of the complete mitochondrial genome in this pedigree revealed the presence of the A3243G mutation and 38 other variants belonging to the Eastern Asian haplogroup M7C. However, none of other mtDNA variants are evolutionarily conserved and implicated to have significantly functional consequence. Thus, the A3243G mutation is the sole pathogenic mtDNA mutation associated with diabetes in this Chinese family.     

Clinical evaluation and mitochondrial DNA sequence analysis in two Chinese families with aminoglycoside-induced and non-syndromic hearing loss

We report here the clinical, genetic, and molecular characterization of two Chinese pedigrees with aminoglycoside-induced and non-syndromic hearing impairment. Clinical evaluation revealed the variable phenotype of hearing impairment including audiometric configuration in these subjects. Penetrances of hearing loss in BJ105 and BJ106 pedigrees are 67% and 33%, respectively. In particular, three of 10 affected matrilineal relatives of BJ105 pedigree had aminoglycoside-induced hearing loss, while seven affected matrilineal relatives in BJ105 pedigree and six affected matrilineal relatives in BJ106 pedigree did not have a history of exposure to aminoglycosides. Sequence analysis of the complete mitochondrial genomes in these pedigrees showed the identical homoplasmic A1555G mutation and distinct sets of mtDNA variants belonging to haplogroups F3 and M7b. These variants showed no evolutionary conservation, implying that mitochondrial haplotype may not play a significant role in the phenotypic expression of the A1555G mutation in these Chinese pedigrees. However, aminoglycosides and nuclear backgrounds appear to be major modifier factors for the phenotypic manifestation of the A1555G mutation in these Chinese families.     

Sensory Ataxic Neuropathy in Golden Retriever Dogs Is Caused by a Deletion in the Mitochondrial tRNATyr Gene

Sensory ataxic neuropathy (SAN) is a recently identified neurological disorder in golden retrievers. Pedigree analysis revealed that all affected dogs belong to one maternal lineage, and a statistical analysis showed that the disorder has a mitochondrial origin. A one base pair deletion in the mitochondrial tRNA^Tyr gene was identified at position 5304 in affected dogs after re-sequencing the complete mitochondrial genome of seven individuals. The deletion was not found among dogs representing 18 different breeds or in six wolves, ruling out this as a common polymorphism. The mutation could be traced back to a common ancestor of all affected dogs that lived in the 1970s. We used a quantitative oligonucleotide ligation assay to establish the degree of heteroplasmy in blood and tissue samples from affected dogs and controls. Affected dogs and their first to fourth degree relatives had 0–11% wild-type (wt) sequence, while more distant relatives ranged between 5% and 60% wt sequence and all unrelated golden retrievers had 100% wt sequence. Northern blot analysis showed that tRNA^Tyr had a 10-fold lower steady-state level in affected dogs compared with controls. Four out of five affected dogs showed decreases in mitochondrial ATP production rates and respiratory chain enzyme activities together with morphological alterations in muscle tissue, resembling the changes reported in human mitochondrial pathology. Altogether, these results provide conclusive evidence that the deletion in the mitochondrial tRNA^Tyr gene is the causative mutation for SAN.     

tRNASer(UCN)7472delC可能是耳聋与癫痫相关的线粒体基因新突变

线粒体DNA突变与许多人类疾病的发病机制相关。文章报道1例典型的患有耳聋与癫痫症状的具有母系遗传特征的中国家系。该家系共3代人, 其中14名母系成员中有3名耳聋患者, 3名癫痫患者, 而其他成员则无临床症状。线粒体全基因组序列分析表明, tRNA^Ser(UCN)基因7472delC新突变和33个多态位点属于东亚单体型B4b1a2。7472delC突变位于tRNA^Ser(UCN)高度保守的T-arm上。而在该区域的相同位点7472insC突变已在多个无遗传相关的家系中被发现与耳聋和癫痫相关。7472insC突变使tRNA代谢和线粒体功能产生缺陷。这样与7472insC突变相近的7472delC突变可能也会以相似机制引起线粒体功能障碍。同时, 在该家系中未发现GJB2基因及其他线粒体基因突变。因此, ^tRNASer(UCN) 7472delC可能是耳聋与癫痫相关的线粒体基因新突变。     

Early disease onset and increased risk of other autoimmune diseases in familial generalized vitiligo

Generalized vitiligo is an autoimmune disorder in which acquired white patches of skin and overlying hair result from autoimmune loss of melanocytes from involved areas. Although usually sporadic, family clustering of vitiligo may occur, in a non-Mendelian pattern typical of multifactorial, polygenic inheritance. Sporadic vitiligo is associated with autoimmune thyroid disease, pernicious anemia, Addison's disease, and lupus; these same disorders occur at increased frequency in patients' first-degree relatives. Here, we studied 133 'multiplex' generalized vitiligo families, with multiple affected family members. The age of onset of vitiligo is earlier in these 'multiplex' families than in patients with sporadic vitiligo. Affected members of the multiplex vitiligo families have elevated frequencies of autoimmune thyroid disease, rheumatoid arthritis, psoriasis, adult-onset insulin-dependent diabetes mellitus, pernicious anemia, and Addison's disease. Probands' unaffected siblings have elevated frequencies of most of these same autoimmune diseases, particularly if the proband had non-vitiligo autoimmune disease. Familial generalized vitiligo is thus characterized by earlier disease onset and a broader repertoire of associated autoimmune diseases than sporadic vitiligo. This mostly likely reflects a greater inherited genetic component of autoimmune susceptibility in these families. These findings have important implications for autoimmune disease surveillance in families in which multiple members are affected with vitiligo.     

Only male matrilineal relatives with Leber's hereditary optic neuropathy in a large Chinese family carrying the mitochondrial DNA G11778A mutation

We report here the characterization of a five-generation large Chinese family with Leber's hereditary optic neuropathy (LHON). Very strikingly, six affected individuals of 38 matrilineal relatives (17 females/21 males) are exclusively males in this Chinese family. These matrilineal relatives in this family exhibited late-onset/progressive visual impairment with a wide range of severity, ranging from blindness to normal vision. The age of onset in visual impairment varies from 17 to 30 years. Sequence analysis of the complete mitochondrial genome in this pedigree revealed the presence of the G11778A mutation in ND4 gene and 29 other variants. This mitochondrial genome belongs to the Southern Chinese haplogroup B5b. We showed that the G11778A mutation is present at near homoplasmy in matrilineal relatives of this Chinese family but not in 164 Chinese controls. Incomplete penetrance of LHON in this family indicates the involvement of modulatory factors in the phenotypic expression of visual dysfunction associated with the G11778A mutation. However, none of other mtDNA variants are evolutionarily conserved and implicated to have significantly functional consequence. Thus, nuclear modifier gene(s) or environmental factor(s) seem to account for the penetrance and phenotypic variability of LHON in this Chinese family carrying the G11778A mutation.     

线粒体ND1基因T3866C突变可能是Leber’s遗传性视神经病和四肢畸形跛行相关的突变

线粒体DNA(Mitochondrial DNA,mtDNA)突变与人类许多疾病的发病机制相关。现报道1个具有典型母系遗传特征的中国人Leber’s遗传性视神经病和四肢畸形跛行的家系。该家系共5代60人,共27名母系成员,其中4人只有Leber’s遗传性视神经病症状,1人呈现四肢畸形跛行症状,4人同时具有上述两种临床症状,而其他成员无临床症状。对先证者的mtDNA全序列进行分析,发现ND1基因T3866C突变位点和43个多态位点,经系统进化树分析属于东亚单体型D4a3。MtDNAND13866位点T-C碱基的改变使ND1亚基第187位进化高度保守的异亮氨酸转变为苏氨酸,从而改变该蛋白的结构,进而影响其功能。在135名正常对照中未发现该突变。因此,线粒体ND1T3866C可能是与Leber’s遗传性视神经病和四肢畸形跛行相关的线粒体基因突变。     

Mitochondrial variants may influence the phenotypic manifestation of Leber's hereditary optic neuropathy-associated ND4 G11778A mutation

We report here the characterization of a five-generation Han Chinese family with Leber's hereditary optic neuropathy (LHON). Strik-ingly, this Chinese family displayed high penetrance and expressivity of visual loss. The average age-of-onset of vision loss was 18 years in this family. Nineteen (11 males/8 females) of 29 matrilineal relatives in this family developed visual loss with a wide range of severity,ranging from blindness to normal vision. Sequence analysis of mitochondrial genome in this pedigree revealed the presence of the ND4 G11778A mutation and 44 other variants belonging to Asian haplogroup M7b. The G11778A mutation is present at homoplasmy in matri-lineal relatives of this Chinese family. Of other variants, the CO1 G6480A, ND5 T12811C and Cytb A15395G located at highly conserved residues of corresponding polypeptides. In fact, these variants were implicated to be involved in other clinical abnormalities. Here, these variants may act in synergy with the primary LHON-associated Gl1778A mutation. Thus, the mitochondrial dysfunction caused by the primary ND4 G11778A mutation may be worsened by these mitochondrial variants. The results imply that the G6480A, T12811C and A15395G variants might have a potential modifier role in increasing the penetrance and expressivity of the primary LHON-associated G11778A mutation in this Chinese family.     

The mitochondrial tRNA(Glu) A14693G mutation may influence the phenotypic manifestation of ND1 G3460A mutation in a Chinese family with Leber's hereditary optic neuropathy

We report here the clinical, genetic, and molecular characterization of one Han Chinese family with maternally transmitted Leber's hereditary optic neuropathy (LHON). Three of seven matrilineal relatives in this family exhibited the variable degree of central vision loss at the age of 12, 14, and 16 years old, respectively. Sequence analysis of the complete mitochondrial DNA in this pedigree revealed the presence of the ND1 G3460A mutation and 47 other variants, belonging to the Asian haplogroup M7b2. The G3460A mutation is present at homoplasmy in matrilineal relatives of this Chinese family. Of other variants, the homoplasmic A14693G mutation is of special interest as it was implicated to be associated with other mitochondrial disorders. This mutation is located at the TpsiC-loop, at conventional position 54 of tRNA(Glu). The uridine at this position (U54), which is highly conserved from bacteria to human mitochondria, has been implicated to be important for tRNA structure and function. Thus, the A14693G mutation may alter the tertiary structure of this tRNA, cause a failure in this tRNA metabolism, thereby worsening the mitochondrial dysfunction associated with the primary G3460A mutation. Therefore, the tRNA(Glu) A14693G mutation may have a potential modifier role in the phenotypic manifestation of the primary LHON-associated G3460A mutation in this Chinese family.     

A new mitochondrial disease associated with mitochondrial DNA heteroplasmy.

A variable combination of developmental delay, retinitis pigmentosa, dementia, seizures, ataxia, proximal neurogenic muscle weakness, and sensory neuropathy occurred in four members of a family and was maternally transmitted. There was no histochemical evidence of mitochondrial myopathy. Blood and muscle from the patients contained two populations of mitochondrial DNA, one of which had a previously unreported restriction site for AvaI. Sequence analysis showed that this was due to a point mutation at nucleotide 8993, resulting in an amino acid change from a highly conserved leucine to arginine in subunit 6 of mitochondrial H(+)-ATPase. There was some correlation between clinical severity and the amount of mutant mitochondrial DNA in the patients; this was present in only small quantities in the blood of healthy elderly relatives in the same maternal line.     

Nuclear mitochondrial pseudogenes as molecular outgroups for phylogenetically isolated taxa: a case study in Sphenodon

'Living fossil' taxa, by definition, have no close relatives, and therefore no outgroup to provide a root to phylogenetic trees. We identify and use a molecular outgroup in the sole extant lineage of sphenodontid reptiles, which separated from other reptiles 230 million years ago. We isolated and sequenced a partial nuclear copy of the mitochondrial cytochrome b gene. We confirm the copy is indeed not mitochondrial, is older than all extant mitochondrial copies in Sphenodon (tuatara), and is therefore useful as a molecular outgroup. Under phylogenetic analysis, the nuclear copy places the root of the tuatara mitochondrial gene tree between the northern and the southern (Cook Strait) groups of islands of New Zealand that are the last refugia for Sphenodon. This analysis supports a previous mid-point rooted mitochondrial gene tree. The mitochondrial DNA tree conflicts with allozyme analyses which place a Cook Strait population equidistant to all northern and other Cook Strait populations. This population on North Brother Island is the only natural population of extant S. guntheri; thus, we suggest that the current species designations of tuatara require further investigation.     

Clinical and molecular analysis of a four-generation Chinese family with aminoglycoside-induced and nonsyndromic hearing loss associated with the mitochondrial 12S rRNA C1494T mutation

We report here the clinical, genetic, and molecular characterization of a four-generation Chinese family with aminoglycoside-induced and nonsyndromic hearing loss. Five of nine matrilineal relatives had aminoglycoside-induced hearing loss. These matrilineal relatives exhibited variable severity and audiometric configuration of hearing impairment, despite sharing some common features: being bilateral and having sensorineural hearing impairment. Sequence analysis of mitochondrial DNA (mtDNA) in the pedigree identified 16 variants and the homoplasmic 12S rRNA C1494T mutation, which was associated with hearing loss in the other large Chinese family. In fact, the occurrence of the C1494T mutation in these genetically unrelated pedigrees affected by hearing impairment strongly indicated that this mutation is involved in the pathogenesis of aminoglycoside-induced and nonsyndromic hearing loss. However, incomplete penetrance of hearing loss indicated that the C1494T mutation itself is not sufficient to produce a clinical phenotype but requires the involvement of modifier factors for the phenotypic expression. Those mtDNA variants, showing no evolutional conservation, may not have a potential modifying role in the pathogenesis of the C1494T mutation. However, nuclear background seems to contribute to the phenotypic variability of matrilineal relatives in this family. Furthermore, aminoglycosides modulate the expressivity and penetrance of deafness associated with the C1494T mutation in this family.     

Recent progress in the genetics of generalized vitiligo

Vitiligo is an acquired disease characterized principally by patchy depigmentation of skin and overlying hair. Generalized vitiligo (GV), the predominant form of the disorder, results from autoimmune loss of melanocytes from affected regions. GV is a “complex trait”, inherited in a non-Mendelian polygenic, multifactorial manner. GV is epidemiologically associated with other autoimmune diseases, both in GV patients and in their close relatives, suggesting that shared genes underlie susceptibility to this group of diseases. Early candidate gene association studies yielded a few successes, such as PTPN22, but most such reports now appear to be false-positives. Subsequent genomewide linkage studies identified NLRPI and XBPI, apparent true GV susceptibility genes involved in immune regulation, and recent genome-wide association studies (GWAS) of GV in Caucasian and Chinese populations have yielded a large number of additional validated GV susceptibility genes.Together, these genes highlight biological systems and pathways that reach from the immune cells to the melanocyte, and provide insights into both disease pathogenesis and potential new targets for both treatment and even prevention of GV and other autoimmune diseases in genetically susceptible individuals.