REPORT Biallelic Mutations in MITF Cause Coloboma, Osteopetrosis, Microphthalmia, Macrocephaly, Albinism, and Deafness Aman George, 1 Dina J. Zand, 2,6 Robert B. Hufnagel, 1 Ruchi Sharma, 3 Yuri V. Sergeev, 1 Janet M. Legare, 4 Gregory M. Rice, 4 Jessica A. Scott Schwoerer, 5 Mariana Rius, 1,7 Laura Tetri, 4 David M. Gamm, 4,5 Kapil Bharti, 3,8 and Brian P. Brooks 1,2,8, * Human MITF is, by convention, called the ‘‘microphthalmia-associated transcription factor’’ because of previously published seminal mouse genetic studies; however, mutations in MITF have never been associated with microphthalmia in humans. Here, we describe a syndrome that we term COMMAD, characterized by coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deaf- ness. COMMAD is associated with biallelic MITF mutant alleles and hence suggests a role for MITF in regulating processes such as optic-fissure closure and bone development or homeostasis, which go beyond what is usually seen in individuals carrying monoallelic MITF mutations. Mouse Mitf encodes a basic helix-loop-helix zipper pro- tein critical for the development of neural-crest-derived melanocytes, neuroectoderm-derived retinal pigment epi- thelium (RPE) cells, and hematopoietic-tissue-derived osteoclasts and mast cells. Autosomal-dominant MITF mutations are associated with two highly overlapping deafness and pigmentation disorders: Waardenburg syn- drome type 2A (WS2A [MIM: 193510]) 1 and Tietz syn- drome (MIM: 103500). 2 Congenital pigmentation defects and sensorineural deafness are attributed to the role of MITF in differentiation and survival of melanocytes in skin and stria vascularis of the cochlea, respectively. 3 Autosomal-recessive or compound-heterozygous inheri- tance of MITF has not been reported previously in humans. Here, we describe two unrelated individuals with com- pound-heterozygous MITF mutations resulting in a com- plex phenotype that we term COMMAD (coloboma, osteo- petrosis, microphthalmia, macrocephaly, albinism, and deafness) and investigate the underlying molecular mech- anisms. Biochemical and functional data for one of the probands demonstrate that mutations do not affect dimer- ization of MITF with other MiT family transcription factors but rather alter nuclear migration and DNA binding of homo- and heterodimers and thus allow the mutant alleles to act as dominant negative. These observations are in agreement with those of previous studies on the Mitf mi/mi mouse model, where homozygosity of the dominant-nega- tive mi allele causes a similar phenotype. 4,5 At last examination, proband I was a 5-year, 3-month- old male with colobomatous microphthalmia and micro- cornea with pannus, dense bilateral cataracts, translucent irides, profound congenital sensorineural hearing loss, and a lack of visible pigment in the hair, skin, and eyes (Fig- ures 1A–1C). Microphthalmia was first detected on prena- tal ultrasound. Head circumference was 56.0 cm (>3 SDs for age), consistent with macrocephaly, and weight (17.3 kg [À0.5 SD]) and height (110.0 cm [0.0 SD]) were normal for his age. He had facial dysmorphisms including frontal bossing, shallow orbits, preauricular pits, and pos- teriorly rotated ears. Skeletal features included a prominent frontal bone, diffuse expansion of the anterior ends of the ribs (Figure 1D, arrow), and bilateral fifth-finger clinod- actyly (data not shown). A radiographic skeletal survey performed at 13 months of age showed osteopetrosis (Figure 1D, arrowheads depict areas of increased bone den- sity). Axial magnetic resonance imaging (MRI) of the brain showed small eyes (~7–8 mm, line on Figure 1E), optic nerves, and chiasm with mild prominence of ventricles, but no other structural abnormalities (Figure 1E). He was delivered at term after an uneventful pregnancy to non- consanguineous parents, both of whom have congenital sensorineural hearing loss, blue irides, fair skin, and prema- ture graying of the hair and are in their third or fourth decade. One male sibling was affected similarly to his parents, and one sister was unaffected (Figure 1F). At last exam, proband II was a 9-month-old female born with severe microphthalmia, profound congenital sensori- neural hearing loss, and a lack of pigment in the hair, skin, and eyes (Figures 1G–1I). She had relative macrocephaly (43.0 cm [0 SD for age]), short stature (65.0 cm [À2 SDs]), 1 Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, MD 20892, USA; 2 Children’s National Medical Center, Wash- ington, DC 20010, USA; 3 Unit on Ocular and Stem Cell Translational Research, National Eye Institute, NIH, Bethesda, MD 20892, USA; 4 Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA; 5 McPherson Eye Research Institute and Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA 6 Present address: Office of New Drugs, Office of Drug Evaluation III Division of Gastroenterology and Inborn Errors Products, US Food and Drug Admin- istration, Silver Spring, MD 20993, USA 7 Present address: School of Marine and Atmospheric Sciences, Stony Brook University, Stony Brook, NY 11790, USA 8 These authors contributed equally to this work *Correspondence: brian.brooks1@nih.gov http://dx.doi.org/10.1016/j.ajhg.2016.11.004. 1388 The American Journal of Human Genetics 99, 1388–1394, December 1, 2016 Ó 2016