Ciliary Dyskinesia, Primary, 36, X-Linked

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Retrieved

2019-09-22

Source

Omim

Trials

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Genes

DNAAF3, DRC1, DNAI1, CCDC151, ARMC4, FOXJ1, DNAAF4, CCDC40, RSPH1, CCDC114, DNAH9, ZMYND10, LRRC6, PIH1D3, CCDC65, CFAP300, CFAP221, DNAH1, CCDC103, RSPH3, TTC25, SPEF2, CFAP298, MCIDAS, HYDIN, DNAAF5, RPGR, SPAG1, GAS8, STK36, OFD1, GAS2L2, CCNO, DNAH5, LRRC56, DNAJB13, DNAH11, CCDC39, DNAI2, SLIT2, AP1B1, C1orf127, RSPH9, NME8, PCBD1, DNAAF1, RSPH4A, AK7, CDO1, DNAH6, CFTR, SIT1, TCTE3, MBL2, RFX1, NME7, TXN, TEKT1, DNAL1, NME5, WDR19, DNAH7, CHD7, DPCD, CDON, NTM, ACVR2B

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A number sign (#) is used with this entry because of evidence that X-linked primary ciliary dyskinesia-36 (CILD36) is caused by hemizygous mutation in the PIH1D3 gene (300933) on chromosome Xq22.

Description

CILD36 is an X-linked recessive disorder characterized by chronic airway disease and recurrent sinopulmonary infections beginning in childhood and caused by defective ciliary function. Affected individuals also have infertility due to defective sperm flagella. About half of patients have laterality defects due to ciliary dysfunction at the embryonic node (summary by Paff et al., 2017).

For a phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (244400).

Clinical Features

Paff et al. (2017) reported 2 unrelated male patients with primary ciliary dyskinesia associated with situs inversus totalis. They had classic features of the disorder, including neonatal respiratory distress, chronic sinusitis, chronic otitis media, and chronic lower respiratory tract infections resulting in bronchiectasis. Nasal nitric oxide was decreased, and videomicroscopy of respiratory epithelial cells and sperm flagella showed completely immotile cilia. Electron microscopy of respiratory cilia showed an absence of outer dynein arms (ODAs) and a possible reduction of inner dynein arms (IDAs). One of the probands had a similarly affected brother and uncle with respiratory symptoms and a history of sub- or infertility due to immotile sperm, although neither had situs inversus.

Inheritance

The transmission pattern of CILD36 in the family reported by Paff et al. (2017) was consistent with X-linked recessive inheritance.

Molecular Genetics

In 2 brothers and their maternal uncle with CILD36, Paff et al. (2017) identified a hemizygous frameshift mutation in the PIH1D3 gene (300933.0001). An unrelated male patient with CILD36 carried a different hemizygous truncating mutation (300933.0002) that occurred de novo. The patients were part of a larger cohort of 75 individuals with CILD who underwent targeted exome sequencing of a panel of 310 genes. Western blot analysis of patient respiratory epithelial cells from the family showed absence of the PIH1D3 protein, consistent with a loss of function. Direct sequencing of the PIH1D3 gene in 40 additional males with PCD with ODA or combined ODA/IDA defects did not identify any additional mutations.

Animal Model

Dong et al. (2014) found that Pih1d3 -/- mice were born at the expected mendelian frequency and showed no overt phenotype. However, Pih1d3 -/- males were sterile due to immobility and fragility of sperm. Pih1d3 -/- females showed normal fertility. Outer dynein arms were almost entirely missing from Pih1d3 -/- sperm, and inner dynein arms were lost in some but not all mutant sperm. Mutant sperm showed reduced content of inner and outer dynein arm proteins. Dong et al. (2014) concluded that Pih1d3 is required for cytoplasmic preassembly of axonemal dyneins in mouse sperm.