ORPHA: 183678, 79430;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19p13.3 | ?Hermansky-Pudlak syndrome 10 | 617050 | Autosomal recessive | 3 | AP3D1 | 607246 |
A number sign (#) is used with this entry because of evidence that Hermansky-Pudlak syndrome-10 (HPS10) is caused by homozygous mutation in the AP3D1 gene (607246) on chromosome 19p13. One such patient has been reported.
Hermansky-Pudlak syndrome-10 (HPS10) is an autosomal recessive multisystem disorder characterized by infantile onset of immunodeficiency, oculocutaneous albinism, and severe neurologic impairment, including severely delayed global development and intractable seizures (summary by Ammann et al., 2016).
For a general phenotypic description and a discussion of genetic heterogeneity of Hermansky-Pudlak syndrome, see HPS1 (203300).
Ammann et al. (2016) reported a boy, born of consanguineous Turkish parents, with severe neurologic impairment, albinism, and immunodeficiency. He developed seizures and dystonic movements with truncal hypotonia in the first weeks of life. The epilepsy progressed over the next few years, with intractable myoclonic and generalized tonic-clonic seizures. He developed recurrent infections at age 8 months, associated with hepatosplenomegaly and severe neutropenia. He also had oculocutaneous albinism with poorly pigmented hair and nystagmus. Other neurologic abnormalities included little developmental progress, reduced otoacoustic potentials, reduced brainstem-evoked response audiometry, no ocular fixation, and poor feeding associated with hypotonia. Brain imaging showed atrophy of the telencephalon, a large arachnoid cyst in the posterior fossa, and poor myelination. Radiographs showed flat acetabulae. The patient also had dysmorphic features apparent since birth, including microcephaly, large, low-set ears, retrognathia with Pierre-Robin sequence, hypotelorism, and flat philtrum. Immunologic work-up showed normal immunoglobulin levels and vaccine response with increased IgE. NK- and T-cell degranulation were impaired, and bone marrow showed hypersegmented neutrophils. Abnormal bleeding was not noted, but Ammann et al. (2016) stated that platelet function was not analyzed and that the patient may have had a subclinical platelet granule defect. The patient died of septic pneumonia at age 3.5 years.
The transmission pattern of HPS10 in the family reported by Ammann et al. (2016) was consistent with autosomal recessive inheritance.
In a boy, born of consanguineous Turkish parents, with HPS10, Ammann et al. (2016) identified a homozygous truncating mutation in the AP3D1 gene (607246.0001). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. The mutation was shown to disrupt assembly of the AP3 complex, consistent with a loss of function, and to putatively cause a defect in the biogenesis and transport of lysosome-related organelles. Ammann et al. (2016) noted the phenotypic similarities to the 'mocha' mouse, which results from a null mutation in the Ap3d1 gene (see ANIMAL MODEL).
The 'mocha' mouse mutant, a model for Hermansky-Pudlak syndrome (203300), shows coat and eye color dilution, reduced levels of renal lysosomal enzymes in urine, and prolonged bleeding due to storage pool deficiency in the dense granules of platelets. Mocha mice have balance problems due to otolith defects and eventually become deaf. They are also hyperactive and have a unique hypersynchronized 6- to 7-Hz electrocortigram. By Southern blot analysis of restriction digests of mocha mouse DNA, Kantheti et al. (1998) determined that mocha is a null allele of the Ap3d1 gene. They observed a lack of AP3 in mocha tissues and reduced levels of the zinc transporter Znt3 (SLC30A3; 602878) in brain, resulting in a lack of zinc-associated Timm historeactivity in hippocampal mossy fibers.
Ammann, S., Schulz, A., Krageloh-Mann, I., Dieckmann, N. M. G., Niethammer, K., Fuchs, S., Eckl, K. M., Plank, R., Werner, R., Altmuller, J., Thiele, H., Nurnberg, P., and 9 others. Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome. Blood 127: 997-1006, 2016. [PubMed: 26744459] [Full Text: https://doi.org/10.1182/blood-2015-09-671636]
Kantheti, P., Qiao, X., Diaz, M. E., Peden, A. A., Meyer, G. E., Carskadon, S. L., Kapfhamer, D., Sufalko, D., Robinson, M. S., Noebels, J. L., Burmeister, M. Mutation in AP-3 delta in the mocha mouse links endosomal transport to storage deficiency in platelets, melanosomes, and synaptic vesicles. Neuron 21: 111-122, 1998. [PubMed: 9697856] [Full Text: https://doi.org/10.1016/s0896-6273(00)80519-x]