Mutations in DNAH1, which Encodes an Inner Arm Heavy Chain Dynein, Lead to Male Infertility from Multiple Morphological Abnormalities of the Sperm Flagella

Abstract

Ten to fifteen percent of couples are confronted with infertility and a male factor is involved in approximately half the cases. A genetic etiology is likely in most cases yet only few genes have been formally correlated with male infertility. Homozygosity mapping was carried out on a cohort of 20 North African individuals, including 18 index cases, presenting with primary infertility resulting from impaired sperm motility caused by a mosaic of multiple morphological abnormalities of the flagella (MMAF) including absent, short, coiled, bent, and irregular flagella. Five unrelated subjects out of 18 (28%) carried a homozygous variant in DNAH1, which encodes an inner dynein heavy chain and is expressed in testis. RT-PCR, immunostaining, and electronic microscopy were carried out on samples from one of the subjects with a mutation located on a donor splice site. Neither the transcript nor the protein was observed in this individual, confirming the pathogenicity of this variant. A general axonemal disorganization including mislocalization of the microtubule doublets and loss of the inner dynein arms was observed. Although DNAH1 is also expressed in other ciliated cells, infertility was the only symptom of primary ciliary dyskinesia observed in affected subjects, suggesting that DNAH1 function in cilium is not as critical as in sperm flagellum.

Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella

“…2 Individuals with multiple morphological abnormalities of the flagella (MMAF) mostly present with a combination of sperm flagellar malformations, which include absent, short, coiled, bent, and/or irregular-caliber flagella and can be assessed by light microscopy. [2][3][4] Furthermore, unassembled sperm fibrous sheaths and a lack of central microtubules and/or dynein arms have been observed by transmission electron microscopy. 3,4 Men with MMAF have been previously reported as having dysplasia of fibrous sheath (DFS) and short tails.…”

“…[2][3][4] Furthermore, unassembled sperm fibrous sheaths and a lack of central microtubules and/or dynein arms have been observed by transmission electron microscopy. 3,4 Men with MMAF have been previously reported as having dysplasia of fibrous sheath (DFS) and short tails. 5,6 The term MMAF was proposed in 2014 to provide a clear definition of the phenotypes in the affected individuals.…”

“…5,6 The term MMAF was proposed in 2014 to provide a clear definition of the phenotypes in the affected individuals. 3 The incidence of MMAF or DFS has not been reported yet but was previously estimated to be higher than that of primary ciliary dyskinesia (PCD [MIM: 244400]; 1 per 10,000-20,000 births). [6][7][8] As a result of severe flagellar abnormalities, MMAF impairs sperm motility and even leads to total immotility.…”

“…2,[10][11][12][13][14] So far, mutations in only three genes, AKAP4 (MIM: 300185), CCDC39 (MIM: 613798), and DNAH1 (MIM: 603332), have been formally identified to cause MMAF in humans. 2,3,15,16 Among them, biallelic DNAH1 mutations in MMAF have been recurrently identified across studies and account for 28%-44% of MMAF cases. 3,17,18 However, the genetic causes or molecular mechanisms in the other half of MMAF cases are still unclear, indicating the genetic heterogeneity of MMAF.…”

“…2,3,15,16 Among them, biallelic DNAH1 mutations in MMAF have been recurrently identified across studies and account for 28%-44% of MMAF cases. 3,17,18 However, the genetic causes or molecular mechanisms in the other half of MMAF cases are still unclear, indicating the genetic heterogeneity of MMAF.…”