Congenital cataract is a highly heterogeneous disorder at both the genetic and the clinical-phenotypic levels. A unique cataract was observed in a 4-generation Chinese family, which was characterized by autosomal dominant inheritance and late-onset. Mutations in the 13 known genes (CRYAA, CRYAB, CRYBB1, CRYBB2, CRYGC, CRYBA1/A3, CRYGD, Connexin50, Connexin46, intrinsic membrane protein LIM2, cytoskeletal protein BFSP2, the major intrinsic protein-MIP and the heat shock factor HSF4) have previously been demonstrated to be the frequent reason for isolated congenital cataracts, but the exact molecular basis and underlying mechanisms of congenital cataract still remain unclear. This study was designed to find whether these 13 genes developed any mutation in the family members and to identify the disease-causing gene. Polymerase chain reaction (PCR) and direct DNA sequence analysis were carried out to detect the 13 genes. The results showed that no mutation causing amino acid alternations was found in these potential candidate genes among all patients in the family, and only several single-nucleotide polymorphisms (SNPs) were identified. A transitional mutation in the fourth intron of CRYBB2 and some silent mutations in the first exon of BFSP2 and CRYGD were found in the cataract family, but further study showed that these mutations could also be found in normal controls. It was concluded that some unidentified genes may underlie the occurrence of late-onset cataract in this family. A genome-wide screening will be carried out in the next study.
Adult ; Cataract ; congenital ; genetics ; China ; DNA Mutational Analysis ; Female ; Genes, Dominant ; Humans ; Male ; Middle Aged ; Pedigree

Centronuclear myopathies are clinically and genetically heterogenous diseases with common histological findings, namely, centrally located nuclei in muscle fibers with a predominance and hypotrophy of type 1 fibers. We describe two cases from one family with autosomal dominant centronuclear myopathy with unusual clinical features that had initially suggested distal myopathy. Clinically, the patients presented with muscle weakness and atrophy localized mainly to the posterior compartment of the distal lower extremities. Magnetic resonance imaging revealed predominant atrophy and fatty changes of bilateral gastrocnemius and soleus muscles. This report demonstrates the expanding clinical heterogeneity of autosomal dominant centronuclear myopathy.
Adolescent ; Female ; *Genes, Dominant ; Humans ; Middle Aged ; Muscle, Skeletal/pathology ; Myopathies, Structural, Congenital/*genetics/*pathology

OBJECTIVETo investigate the potential genetic mode of aggressive periodontitis (AgP) in Chinese Han nationality.

METHODSA total of 233 subjects from 73 nuclear families were recruited. All probands were diagnosed according to the criteria of AgP in 1999 classification of periodontal diseases. Ninety parents, 35 siblings and three grandparents and two offspring were examined based on full-mouth periodontal chartings (including parameter of probing depths, attachment loss, bleeding on probing at six sites per tooth) and full-mouth periapical radiographs. The genetic ratio was calculated and analyzed by the methods of Edwards and simple segregation.

RESULTSThe prevalence of AgP in probands' siblings was close to the square root of the prevalence of general population. The segregation ratio was 0.2419, which was close to the theoretical ratio for autosomal recessive inheritance. However, autosomal dominant inheritance could not be rejected in families whose parent(s) suffered from severe chronic periodontitis.

CONCLUSIONSThe genetic heterogeneity of AgP existed in Chinese Han nationality. The genetic mode was autosomal recessive inheritance in general, and autosomal dominant inheritance could not be excluded in families whose parent(s) suffered from severe chronical periodontitis. The results imply the genetic heterogeneity of AgP, and further demonstrate that AgP was a multifactorial disease with major genetic component in the disease etiology.

Aggressive Periodontitis ; epidemiology ; genetics ; Asian Continental Ancestry Group ; genetics ; Chronic Periodontitis ; epidemiology ; genetics ; Female ; Genes, Dominant ; Genes, Recessive ; Genetic Heterogeneity ; Humans ; Male ; Pedigree ; Prevalence ; Surveys and Questionnaires

OBJECTIVE: To investigate the clinical and genetical characteristics of a Chinese family with an autosomal-dominant inherited high-frequency sensorineural hearing loss. METHOD: Pedigree was drawn after investigation. Fifeteen family members were checked up, and detailed audiological examination was performed. RESULT: The proband of the kindred had been diagnosed with senserineural hearing loss. A Chinese family SX-G087 with non-sysdromic hearing loss was ascertained. The inheritance pattern of this family is autosomal dominant based on the investigated information. The affected members showed postlingual, progressive, bilateral moderate to severe sensorineural hearing impairment. The age of onset varied from 20 to 35 years. The hearing loss began at high frequencies, and lower frequencies became involved with increasing age. CONCLUSION Pedigree analysis suggested an autosomal-dominant inheritance pattern in this family. The information should facilitate linkage analysis and positional cloning for the causative gene of this family.
Adult ; Age of Onset ; Asian Continental Ancestry Group ; China ; Genes, Dominant ; Hearing Loss, Sensorineural ; genetics ; Humans ; Inheritance Patterns ; Pedigree ; Young Adult

OBJECTIVETo map the disease-causing gene in a Chinese family with autosomal dominant retinitis pigmentosa.

METHODSTwenty-seven micro-satellite markers were randomly selected from the region around the known loci of causative genes, and haplotypes were determined by ABI3100 genetic analyzer. Two-point linkage analysis was performed using MLINK.

RESULTSThe Lod score of each marker vs adRP was below 1.

CONCLUSIONThe phenotype of this family may not be caused by mutation of the known disease-causing genes.

Asian Continental Ancestry Group ; genetics ; China ; Female ; Genes, Dominant ; Genetic Linkage ; Genetic Testing ; Humans ; Male ; Microsatellite Repeats ; genetics ; Mutation ; Pedigree ; Phenotype ; Retinitis Pigmentosa ; diagnosis ; genetics ; pathology

OBJECTIVETo investigate the gene mutations of CHRNB2 and CHRNA2 in Chinese population with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE).

METHODSOne hundred and six Han nationality patients (74 sporadic and 32 familial) were recruited and studied. Mutational screening was performed by sequencing all the 6 coding exons of the CHRNB2 gene and exons 6 and 7 of the CHRNA2 gene including the donor and acceptor splice sites.

RESULTSThe results excluded the involvement of all known published mutations of the CHRNB2 and CHRNA2 genes. However, a novel synonymous mutation c.483C>T (H161H) and a single nucleotide polymorphism (c.1407C>G) of CHRNB2 gene were detected in two ADNFLE sporadic patients respectively. The nucleotide variation H161H was heterozygous and absent in 200 healthy control samples. The mutation was also found in the proband's unaffected mother.

CONCLUSIONOur study suggests that the mutations of CHRNB2 and CHRNA2 genes may be rare in Chinese ADNFLE population. The novel synonymous mutation of H161H has not been reported previously and its impact on the pathogenesis of ADNFLE needs to be further studied.

Asian Continental Ancestry Group ; genetics ; Child ; Child, Preschool ; DNA Mutational Analysis ; Epilepsy, Frontal Lobe ; genetics ; Female ; Genes, Dominant ; Humans ; Male ; Mutation ; Receptors, Nicotinic ; genetics

OBJECTIVE: To investigate the molecular genetic mechanism of Charcot- Marie-Tooth (CMT) disease in a pedigree. METHODS: Genomic DNA was extracted from the peripheral blood of the family members of a pedigree with autosomal dominant CMT disease, and 65 candidate genes of the proband were screened using target exon capture and the next generation sequencing, and the suspicious genes were verified using Sanger sequencing. PolyPhen-2, PROVEAN and SIFT software were used to predict the function of the mutant genes, and PyMOL-1 software was used to simulate the mutant protein structure. RESULTS: A heterozygous missense mutation [c.371A>G (p.Y124C)] was detected in exon 3 of gene of the proband. This heterozygous mutation was also detected in both the proband's mother and her brother, but not in her father. Multiple sequence alignment analysis showed that tyrosine at codon 124 of GDAP1 protein was highly conserved. All the 3 prediction software predicted that the mutation was harmful. Molecular structure simulation showed a weakened interaction force between the amino acid residues at codon 124 and the surrounding amino acid residues to affect the overall stability of the protein. CONCLUSIONS The mutation of gene may be related to the pathogenesis of autosomal dominant AD-CMT in this pedigree. The newly discovered c.371A>G mutation (p.Y124C) expands the mutation spectrum of gene, but further study is needed to clarify the underlying pathogenesis.
Amino Acids ; Charcot-Marie-Tooth Disease ; genetics ; Female ; Genes, Dominant ; genetics ; Heterozygote ; High-Throughput Nucleotide Sequencing ; methods ; Humans ; Male ; Mutation, Missense ; Nerve Tissue Proteins ; genetics ; Pedigree ; Software

OBJECTIVETo map the gene locus in a Chinese pedigree with autosomal dominant nonsyndromic hearing loss.

METHODSA genome wide screening was performed with 394 microsatellite markers distributed with an average spacing of 10 cM (ABI Prism Linkage Mapping Set 2, Applied Biosystems, Foster City, CA, U.S.A.).

RESULTSAffected family members showed a bilateral, symmetrical, progressive neurosensory deafness. Significant linkage was found to marker D1 S937 (maximum two point LOD score of 5. 71 at theta = 0.05) on chromosome 11q. The position of the novel deafness locus, DFNA11, was delimited by analysis of the recombinant haplotypes (D11S165-D11S1874). This analysis placed DFNA11 between the proximal marker D11S1314 and the distal marker D11S898, which define a critical interval of 25.34 cM.

CONCLUSIONSMapping of the DFNA11 locus further confirms the great genetic heterogeneity underlying the autosomal dominant forms of hereditary deafness. Reports of more families with hearing impairment linked to this locus should contribute to the identification of the responsible gene, providing insights into the auditory function and the molecular pathophysiology of age related hearing loss.

Adult ; Aged ; Chromosome Mapping ; Deafness ; congenital ; genetics ; Female ; Genes, Dominant ; Haplotypes ; Humans ; Male ; Microsatellite Repeats ; Middle Aged ; Myosins ; genetics ; Pedigree ; Young Adult

BACKGROUNDCongenital cataract is a sight-threatening disease that affects about 1 - 6 cases per 10000 live births and causes 10% - 30% of all blindness in children. About 25% of all cases are due to genetic defects. We identified autosomal dominant congenital coralliform cataracts-related genetic defect in a four-generation Chinese family.

METHODSComplete ophthalmological examinations were performed prior to lens extraction. Lens samples were then studied by electron microscopy. Genomic DNA from family members were examined using whole-genomic linkage analysis, with two-point logarithm of odds (LOD) scores calculated using the Linkage program package (version 5.1). Mutation analysis of candidate genes was performed by direct sequencing. Finally, a three-dimensional protein model was predicted using Swiss-Model (version 2.0).

RESULTSEleven of the 23 examined individuals had congenital cataracts. Ultrastructure studies revealed crystal deposits in the lens, and granules extensively dispersed in transformed lens fiber cells. The maximum two-point LOD score, 3.5 at theta = 0.1, was obtained for the marker D2S325. Mutation analysis of the gamma-crystallin (CRYG) gene cluster identified a mutation (P23T) in exon 2 of gammaD-crystallin (CRYGD). Protein structure modeling demonstrated that the P23T mutation caused a subtle change on the surface of the gammaD protein.

CONCLUSIONSThe results suggest that the coralliform cataract phenotype is due to a mutated CRYGD gene, and that this sequence change is identical to one reported by Santhiya to be related to another distinct clinical condition, lamellar cataract. This study provides evidence that this same genetic defect may be associated with a different phenotype. This is the first report identifying the genetic defect associated with an autosomal dominant congenital coralliform cataract.

Cataract ; genetics ; pathology ; Female ; Genes, Dominant ; Genetic Linkage ; Humans ; Lens, Crystalline ; ultrastructure ; Male ; Microscopy, Electron ; Mutation, Missense ; gamma-Crystallins ; chemistry ; genetics

INTRODUCTIONRetinitis pigmentosa (RP) describes a group of inherited disorders characterised by progressive retinal dysfunction, cell loss and atrophy of retinal tissue. RP demonstrates considerable clinical and genetic heterogeneity, with wide variations in disease severity, progression, and gene involvement. We studied a large family with RP to determine the pattern of inheritance and identify the disease-causing mutation, and then to describe the phenotypic presentation of this family.

MATERIALS AND METHODSOphthalmic examination was performed on 46 family members to identify affected individuals and to characterise the disease phenotype. Family pedigree was obtained. Some family members also had fundus photographs, fluorescein angiography, and/or optical coherence tomography (OCT) analysis performed. Genetic linkage was performed using short tandem repeat (STR) polymorphic markers encompassing the known loci for autosomal dominant RP. Finally, DNA sequencing was performed to identify the mutation present in this family.

RESULTSClinical features included nyctalopia, constriction of visual fields and eventual loss of central vision. Sequence analysis revealed a G-to-T nucleotide change in the Rhodopsin gene, predicting a Gly-51-Val substitution.

CONCLUSIONSThis large multi-generation family demonstrates the phenotypic variability of a previously identified autosomal dominant mutation of the Rhodopsin gene.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; Female ; Genes, Dominant ; Humans ; Male ; Middle Aged ; Mutation ; Pedigree ; Retinitis Pigmentosa ; genetics ; Rhodopsin ; genetics