Founder effects of the homogentisate 1,2-dioxygenase (HGD) gene in a gypsy population and mutation spectrum in the gene among alkaptonuria patients from India.

INTRODUCTION: Alkaptonuria (AKU) is a rare metabolic disease. The global incidence is 1:100,000 to 1:250,000. However, identification of a founder mutation in a gypsy population from India prompted us to study the prevalence of AKU in this population and to do molecular typing in referred cases of AKU from the rest of India. OBJECTIVE: To determine the prevalence of AKU in the gypsy population predominantly residing in the seven districts of Tamil Nadu. To determine the molecular characteristic of AKU cases referred to our clinic from various parts of India. METHOD: Urine spot test to detect homogentisic acid followed by quantitative estimation using high-performance liquid chromatography in 499 participants from the gypsy population and confirming the founder mutation in those with high levels by sequencing. Sequence the homogentisate 1,2-dioxygenase (HGD) gene to identify mutations and variants in 29 AKU non-gypsy cases. RESULTS: The founder mutation was detected in homozygous state in 41/499 AKU-affected individuals of the gypsy community giving a high prevalence of 8.4%. Low back pain, knee pain, and eye and ear pigmentation were the most common symptoms and signs respectively. The commonest mutation identified in the non-gypsy AKU cases was p.Ala122Val. CONCLUSION: High prevalence of AKU in the inbred gypsy population at 8.4% was detected confirming the founder effect. Urine screening provided a cost-effective method to detect the disease early. Mutation spectrum is varied in the rest of the Indian population. This study identified maximum number of mutations in exon 6 of the HGD gene. Key Points • High prevalence (8.4%) of alkaptonuria (AKU) in the gypsy population due to founder mutation in the HGD gene. • Inbreeding exemplifies the founder effects of this rare genetic disorder. • Urinary screening is a cost-effective method in this community for early detection of AKU and intervention. • The mutation spectrum causing AKU is diverse in the rest of the Indian population.

Two novel mutations in the KHDC3L gene in Asian patients with recurrent hydatidiform mole.

Recurrent hydatidiform mole (RHM) is defined by the occurrence of repeated molar pregnancies in affected women. Two genes, NLRP7 and KHDC3L, play a causal role in RHM and are responsible for 48-80% and 5% of cases, respectively. Here, we report the results of screening these two genes for mutations in one Iranian and one Indian patient with RHM. No mutations in NLRP7 were identified in the two patients. KHDC3L sequencing identified two novel protein-truncating mutations in a homozygous state, a 4-bp deletion, c.17_20delGGTT (p.Arg6Leufs*7), in the Iranian patient and a splice mutation, c.349+1G>A, that affects the invariant donor site at the junction of exon 2 and intron 2 in the Indian patient. To date, only four mutations in KHDC3L have been reported. The identification of two additional mutations provides further evidence for the important role of KHDC3L in the pathophysiology of RHM and increases the diversity of mutations described in Asian populations.

Lack of any association of the CTLA-4 +49 G/A polymorphism with breast cancer risk in a North Indian population.

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an important protein involved in the regulation of the immune system. The +49 G/A polymorphism is the only genetic variation in the CTLA-4 gene that causes an amino acid change in the resulting protein. It is therefore the most extensively studied polymorphism among all CTLA-4 genetic variants and contributions to increasing the likelihood of developing cancer are well known in various populations, especially Asians. However, there have hiterto been no data with respect to the effect of this polymorphism on breast cancer susceptibility in our North Indian population. We therefore assayed genomic DNA of 250 breast cancer subjects and an equal number of age-, sex- and ethnicity-matched healthy controls for the CTLA-4 +49 G/A polymorphism but no significant differences in either the gene or allele frequency were found. Thus the CTLA-4 +49 G/A polymorphism may be associated with breast cancer in other Asians, but it appears to have no such effect in North Indians. The study also highlights the importance of conducting genetic association studies in different ethnic populations.

Molecular studies of achondroplasia.

BACKGROUND: Achondroplasia (ACH) is the most frequent form of short-limbed dwarfism, caused by mutations in the FGFR3 gene. It follows an autosomal dominant inheritance, though most cases are sporadic. The molecular techniques are the only available methods to confirm the diagnosis of a skeletal dysplasia. Clinical and radiological features are only suggestive and not confirmatory. The present study was conducted to find out how often the clinical diagnosis of achondroplasia is verified on molecular studies. MATERIALS AND METHODS: From 1998 through 2007, we carried out molecular analysis for the two common mutations in the FGFR3 gene in 130 cases clinically suspected to have ACH. RESULTS: A diagnostic mutation was identified in 53 (40.8%) cases. The common mutation (1138G>A) was present in 50 (94.7%) of the positive cases, while the rare 1138 G>C substitution was found in three (5.3%). CONCLUSION: This study shows that confirmation of clinical diagnosis of ACH by molecular genetic testing is essential to distinguish it from other skeletal dysplasias, to plan therapeutic options, and to offer genetic counseling. Management (medical and surgical) in patients confirmed to have ACH, is briefly discussed.