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.
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
Ai-Hua
AH
Wei
Dong-Jie
DJ
Zang
Zhe
Z
Zhang
Xuan-Zhu
XZ
Liu
Xin
X
He
Lin
L
Yang
Yi
Y
Wang
Zhi-Yong
ZY
Zhou
Ming-Rong
MR
Zhang
Lan-Lan
LL
Dai
Xiu-Min
XM
Yang
Wei
W
Li
D000293:Adolescent; D000328:Adult; D016115:Albinism, Oculocutaneous / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D000818:Animals; D017920:Antiporters / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics; D016022:Case-Control Studies; D002675:Child, Preschool; D004195:Disease Models, Animal; D059472:Exome / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D022861:Hermanski-Pudlak Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins / Q000235:genetics; D008297:Male; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D020460:Melanosomes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D012867:Skin / Q000378:metabolism / Q000473:pathology; D033921:Vesicular Transport Proteins
D017920:Antiporters; C513476:Bloc1s6 protein, mouse; D002352:Carrier Proteins; C554282:Hps6 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins; C506584:SLC24A5 protein, human; C583211:SLC24A5 protein, mouse; D033921:Vesicular Transport Proteins