Mutation of SLC35D3 causes metabolic syndrome by impairing dopamine signaling in striatal D1 neurons.

Obesity is one of the largest health problems facing the world today. Although twin and family studies suggest about two-thirds of obesity is caused by genetic factors, only a small fraction of this variance has been unraveled. There are still large numbers of genes to be identified that cause variations in body fatness and the associated diseases encompassed in the metabolic syndrome (MetS). A locus near a sequence tagged site (STS) marker D6S1009 has been linked to obesity or body mass index (BMI). However, its genetic entity is unknown. D6S1009 is located in the intergenic region between SLC35D3 and NHEG1. Here we report that the ros mutant mice harboring a recessive mutation in the Slc35d3 gene show obesity and MetS and reduced membrane dopamine receptor D1 (D1R) with impaired dopamine signaling in striatal neurons. SLC35D3 is localized to both endoplasmic reticulum (ER) and early endosomes and interacts with D1R. In ros striatal D1 neurons, lack of SLC35D3 causes the accumulation of D1R on the ER to impair its ER exit. The MetS phenotype is reversible by the administration of D1R agonist to the ros mutant. In addition, we identified two mutations in the SLC35D3 gene in patients with MetS, which alter the subcellular localization of SLC35D3. Our results suggest that the SLC35D3 gene, close to the D6S1009 locus, is a candidate gene for MetS, which is involved in metabolic control in the central nervous system by regulating dopamine signaling.

Prenatal genotyping of four common oculocutaneous albinism genes in 51 Chinese families.

Oculocutaneous albinism (OCA) is an autosomal recessive disorder characterized by hypopigmentation in eyes, hair and skin, accompanied with vision loss. Currently, six genes have been identified as causative genes for non-syndromic OCA (OCA-1∼4, 6, 7), and ten genes for syndromic OCA (HPS-1-9, CHS-1). Genetic counseling of 51 Chinese OCA families (39 OCA-1 with mutations in the TYR gene, 6 OCA-2 with mutations in the OCA2 gene, 4 OCA-4 with mutations in the SLC45A2 gene, 1 HPS-1 (Hermansky-Pudlak syndrome-1) with mutation in the HPS1 gene, and 1 mixed OCA-1 and OCA-4) led us to perform the prenatal genetic testing of OCA using amniotic fluid cells through the implementation of our optimized strategy. In our cohort, eleven previously unidentified alleles (PUAs) (5 in TYR, 2 in OCA2, and 4 in SLC45A2) were found. Three missense PUAs (p.C112R, p.H363R and p.G379V of TYR) and one in-frame deletional PUA (p.S222del of SLC24A5) led to fetuses with OCA when co-inherited with other disease causative alleles. Three PUAs (p.P152H and p.W272X of TYR, p.A486T of SLC24A5) identified in the OCA probands did not co-transmit with known pathological alleles and thus gave rise to unaffected fetuses. Four PUAs (p.Q83X and p.A658T of TYR, p.G161R and p.G366R of SLC24A5) did not transmit to the unaffected fetuses. In addition, the in vitro transfection assays showed that the p.S192Y variant of TYR produced less pigment compared to the wild-type allele. A fetus with a digenic carrier of OCA-1 and OCA-4 was unaffected. In combination with functional assays, the family inheritance pattern is useful for the evaluation of pathogenicity of PUAs and genetic counseling of OCA.

Exome sequencing identifies SLC24A5 as a candidate gene for nonsyndromic oculocutaneous albinism.

Oculocutaneous albinism (OCA) is a heterogeneous and autosomal recessive disorder with hypopigmentation in the eye, hair, and skin color. Four genes, TYR, OCA2, TYRP1, and SLC45A2, have been identified as causative genes for nonsyndromic OCA1-4, respectively. The genetic identity of OCA5 locus on 4q24 is unknown. Additional unknown OCA genes may exist as at least 5% of OCA patients have not been characterized during mutational screening in several populations. We used exome sequencing with a family-based recessive mutation model to determine that SLC24A5 is a previously unreported candidate gene for nonsyndromic OCA, which we designate as OCA6. Two deleterious mutations in this patient, c.591G>A and c.1361insT, were identified. We found apparent increase of immature melanosomes and less mature melanosomes in the patient's skin melanocytes. However, no defects in the platelet dense granules were observed, excluding typical Hermansky-Pudlak syndrome (HPS), a well-known syndromic OCA. Moreover, the SLC24A5 protein was reduced in steady-state levels in mouse HPS mutants with deficiencies in BLOC-1 and BLOC-2. Our results suggest that SLC24A5 is a previously unreported nonsyndromic OCA candidate gene and that the SLC24A5 transporter is transported into mature melanosomes by HPS protein complexes.

Hereditary benign telangiectasia without family history in China.

A case of hereditary benign telangiectasia without family history was reported. A 39-year-old woman presented with small and tiny telangiectases on the face, neck, upper trunk and forearms at birth. The numbers and sizes of the lesions increased gradually and she had no hemorrhagic diathesis and systemic diseases. No similar patients were found in her family. Upon physical examination, telangiectases were found on the face, neck, upper trunk and forearms; and a telangiectatic erythema was found on the right forearm 25 mm × 40 mm in size. Histopathology examination showed a normal epidermis and dilation of the capillaries at upper dermis. Hereditary benign telangiectasia without family history was diagnosed.